Pharmaceutical compositions of adsorbates of amorphous drugs and lipophilic microphase-forming materials

ABSTRACT

A pharmaceutical composition comprises a solid adsorbate comprising a drug adsorbed onto a substrate and a lipophilic microphase-forming material. The solid adsorbate may also be co-administered with a lipophilic microphase-forming material to an in vivo use environment. The compositions of the present invention enhance the concentration of drug in a use environment.

This application is filed claiming priority from U.S. ProvisionalApplication No. 60/492,410 filed Aug. 4, 2003.

FIELD OF THE INVENTION

The present invention relates to pharmaceutical compositions comprising(1) a solid adsorbate comprising a low-solubility drug adsorbed onto asubstrate, and (2) a lipophilic microphase-forming material thatenhances the concentration of the drug in a use environment.

BACKGROUND OF THE INVENTION

Low-solubility drugs often show poor bioavailability or irregularabsorption, the degree of irregularity being affected by factors such asdose level, fed state of the patient, and form of the drug. Increasingthe bioavailability of low-solubility drugs has been the subject of muchresearch. Increasing bioavailability depends on improving theconcentration of dissolved drug in solution to improve absorption.

It is well known that the amorphous form of a low-solubility drug thatis capable of existing in either the crystalline or amorphous form maytemporarily provide a greater aqueous concentration of drug relative tothe equilibrium concentration obtained by dissolution of the drug in ause environment. Such amorphous forms may consist of the amorphous drugalone, a dispersion of the drug in a matrix material, or the drugadsorbed onto a substrate. It is believed that such amorphous forms ofthe drug may dissolve more rapidly than the crystalline form, oftendissolving faster than the drug can precipitate from solution. As aresult, the amorphous form may temporarily provide a greater-thanequilibrium concentration of drug.

While such amorphous forms may show initially enhanced concentration ofthe drug in a use environment, nevertheless the improved concentrationis often short-lived. Typically, the initially enhanced drugconcentration is only temporary and quickly returns to the lowerequilibrium concentration.

One problem with using the amorphous form of a drug is that the soliddrug may not be stable physically in the amorphous form. Often thecrystalline form of the drug has a lower free energy, and thus overtime, the amorphous drug will tend to crystallize. The rate ofcrystallization may be influenced by storage conditions, such astemperature and humidity, as well as the constituents of thecomposition.

Babcock, et al. in commonly assigned U.S. patent application Ser. No.10/173,987 published as US 2003/0054037, incorporated herein byreference, disclose a solid adsorbate comprising a low-solubility drugadsorbed onto a substrate, the substrate having a surface area of atleast 20 m²/g, wherein at least a major portion of the drug in theadsorbate is amorphous. The composition provides enhanced drugconcentrations when administered to an aqueous environment of use. Inanother embodiment, the composition comprises a solid adsorbate of alow-solubility drug adsorbed onto a substrate mixed with aconcentration-enhancing polymer. In yet another embodiment, thecomposition comprises a solid adsorbate and a concentration-enhancingpolymer adsorbed onto a substrate.

Babcock, et al. disclose that the adsorbate may be mixed withsurfactants or surface-active agents to increase the rate of dissolutionby facilitating wetting, formation of micelles, or inhibitingcrystallization or precipitation of the drug. Such materials cancomprise up to 5 wt % of the composition.

Takeuchi, Chem. Pharm. Bull. 35(9) 3800-3806 (1987), discloses spraydried compositions of the drug tolbutamide and very fine hydrophilicsilica particles, Aerosil® 200. A 1:1 weight solution of tolbutamide andAerosil® 200 was sprayed from a solution of 2% ammonia water. Theauthors indicate that at least some of the drug was amorphous.

Reuter et al., U.S. Pat. No. 4,835,186 discloses a spray driedsuspension of colloidal silica in a lower alkanol solution of ibuprofenand cellulose acetate phthalate. The examples disclose spray driedcompositions comprising ibuprofen, CAP, colloidal silica and a smallamount of castor oil, spray dried from a solution of ethyl acetate andisopropyl alcohol.

WO 01/00180A1 discloses a self-emulsifying drug (SED) compositioncomprising a o-(chloroacetylcarbamoyl)fumigillol, a pharmaceuticallyacceptable carrier comprising an oily constituent and at least onesurfactant, and a stabilizing component, the stabilizing componentcomprising water, an acid, and an adsorbent core complex forming agent.The pharmaceutically acceptable carrier having the drug can be filled,mixed, adsorbed, filtered, or otherwise combined with the adsorbent orcomplex forming agent. Exemplary adsorbents include active charcoal andsilica gel.

Monkhouse et al. (J. Pharm. Sci., Vol. 61, No. 9, 1972), discloseforming adsorbents by mixing a drug and water insoluble adsorbent suchas fumed silicon dioxide or precipitated silicic acid, adding asufficient quantity of an organic solvent to dissolve the drug, and thenevaporating the solvent by a stream of filtered air.

Yamamoto et al., “Adsorption of Pharmaceutical Organic Compounds ontoPorous Materials,” (in Surfaces of Nanoparticles and Porous Materals,Scwarz and Contescu eds, 1999) reviews among other things, improvingdissolution of drugs by using porous materials to form drug that is theamorphous state.

Nevertheless, what is still desired is a composition that may enhancethe dissolution and/or bioavailability of poorly soluble drugs. Theseneeds and others that will become apparent to one of ordinary skill aremet by the present invention, which is summarized and described indetail below.

BRIEF SUMMARY OF THE INVENTION

The present invention overcomes the drawbacks of the prior art byproviding a composition comprising (1) a solid adsorbate comprising alow-solubility drug adsorbed onto a substrate, wherein at least a majorportion of the drug is amorphous, and (2) a lipophilicmicrophase-forming material. The combination of a solid adsorbate and alipophilic microphase-forming material results in improved dissolvedconcentration of the drug in the aqueous use environment, and in someembodiments a surprising synergy. A concentration-enhancing polymer mayoptionally be incorporated into the solid adsorbate or mixed with thecomposition of the present invention.

In another aspect of the invention, a solid adsorbate comprising alow-solubility drug adsorbed onto a substrate, wherein at least a majorportion of the drug is amorphous, is co-administered with a lipophilicmicrophase-forming material to an in vivo use environment. The solidadsorbate may optionally include a concentration-enhancing polymer, or aconcentration-enhancing polymer may optionally be co-administered withthe solid adsorbate and lipophilic microphase-forming material. Anotheraspect of the invention comprises a kit comprising a solid adsorbatecomprising a low-solubility drug adsorbed onto a substrate and alipophilic microphase-forming material.

The present inventors have found that the ability of a drug/substrateadsorbate to enhance the concentration of drug in a use environment maybe significantly improved by the addition of certain lipophilicmicrophase-forming materials. These lipophilic microphase-formingmaterials, when administered to an aqueous use environment such as theGI tract, form a plurality of small microphases, or so-called“lipophilic microphases.” The lipophilic microphase-forming materialsare chosen such that (1) they are water immiscible, (2) the drug has ahigh partition coefficient between the lipophilic microphase-formingmaterial and the aqueous use environment, and (3) they form smalllipophilic microphases in the aqueous use environment.

Without wishing to be bound by any particular theory, the presentinventors believe that when a composition of the present inventioncomprising an adsorbate comprising a low-solubility drug and ahigh-surface-area substrate, wherein at least a major portion of thedrug is amorphous, and a lipophilic microphase-forming material areintroduced to a use environment such as the GI tract, the drug may bepresent in several different species. When the aqueous use environmentis either the GI tract of an animal, or an in vitro use environment thatsimulates the GI tract of an animal, it is believed that at least fivedifferent drug species are formed: (1) free drug; (2) drug presentwithin bile salt micelles that are naturally occurring in the GI tract;(3) drug adsorbed to small particles of the high-surface-area substrate;(4) precipitate; and (5) drug in lipophilic microphases.

As used herein, the term “free drug” refers to drug molecules which aredissolved in the aqueous solution and are generally either monomeric orclusters of no more than about 100 molecules. “Precipitate” is a generalterm for any relatively large particulates that form and fall out ofsolution, either naturally or upon centrifugation. Such precipitate maycomprise one or more or all of the following forms: (1) crystallinedrug; (2) amorphous drug; and/or (3) drug adsorbed to the substrate thatis present as particles that have a sufficient density and size so as todrop out of solution (typically greater than about 5 to 10 microns inaverage diameter). As used herein, the term “total dissolved drug”refers to the total concentration of drug in a use environment that isnot present as precipitate. Thus, “total dissolved drug” refers to thesum of all drug species that are present except for precipitate. Thesespecies include, but are not limited to, free drug, drug within bilesalt micelles, drug absorbed to small particles, and drug in thelipophilic microphases.

Generally, it is desirable to increase the free drug concentration inthe GI tract. Without wishing to be bound by any particular theory ormechanism of action, it is believed that primarily free drug is directlyabsorbed from the GI tract into the blood. The absorption rate of a drugfrom the GI tract to the blood is therefore generally proportional tothe free drug concentration at the intestinal membrane surface. Drugpresent in the other species generally must first convert to the freedrug form in order to be absorbed. In addition, for many lipophilicdrugs, the rate limiting step for absorption can be diffusion across themucin or mucus layer that coats the lipid membrane of the intestinalWall. This layer is often referred to as the “unstirred water layer.”When diffusion across this layer is rate limiting, the absorption rateof drug is proportional to the sum of the free drug and drug in speciessuch as bile-salt micelles or lipophilic microphases, which can diffuseacross the unstirred water layer, normalized for their respectivediffusion coefficients.

The present invention provides one or more of the following advantagesover prior methods for enhancing the concentration and bioavailabilityof low-solubility drugs. The lipophilic microphases are capable ofsufficiently solubilizing the drug in the use environment to enhancebioavailability. In some cases, the lipophilic microphases are thoughtto be (1) highly mobile, meaning that they may diffuse more rapidly thanprecipitate throughout the use environment and particularly through theunstirred water layer of the intestinal wall; and (2) labile, meaningthat the drug may rapidly convert back and forth between the lipophilicmicrophases and free drug. Because the lipophilic microphases solubilizethe drug, the lipophilic microphases may reduce the formation of drugprecipitate and increase the amount of total dissolved drug. Thelability of the lipophilic microphases may also increase the rate ofresupply of free drug in the use environment. As free drug is absorbed,drug present in the lipophilic microphases may rapidly convert to freedrug, thus maintaining a sustained free drug concentration. When thelipophilic microphases are small, their high mobility may also increasethe rate of drug absorption through the intestinal wall by increasingthe transport rate of the drug through the unstirred water layer of theintestinal wall. In combination, these properties may greatly enhancethe rate and extent of drug absorption (e.g., bioavailability).

In addition, the compositions may also have the advantage of providingmore similar absorption levels between the fed and fasted state of a setof patients, as well as less variation in the level of absorption frompatient to patient. A problem when dosing low-solubility drugs is thatthe absorption of the drug may vary widely between the fed and fastedstate of the patient. This variation in absorption is due in part tovariation in the level of bile-salt micelles between the fasted and fedstates. The lipophilic microphase-forming materials of the presentinvention can function in a similar manner as bile-salt micelles.

As mentioned above, it is well known in the art that in the fed state,the concentration of bile-salt micelles present in the GI tract isgreater than the concentration present in the fasted state. Theinventors believe that this difference in the concentration of bile-saltmicelles in the GI tract in the fed versus fasted state may account, atleast in part, for the fed/fasted differences in bioavailabilityobserved for many pharmaceutical compositions. The compositions of thepresent invention comprising a drug/substrate adsorbate and a lipophilicmicrophase-forming material may minimize this fed/fasted difference inbioavailability. The compositions tend to equalize the amount of drugpresent in highly labile, highly mobile species between the fed andfasted state, and thus provide a more uniform bioavailability betweenthe fed and fasted state. This equalization can be understood via ahypothetical example in which lipophilic drug with an aqueous solubilityof 1 μgA/mL and a bile salt aqueous partition coefficient of 200, isdosed in the fed and fasted states with and without lipophilicmicrophase-forming material (“μgA” refers to the amount of active drugin micrograms). The lipophilic microphase-forming material is dosed at100 mg into a GI volume of 100 mL in the fasted state and 200 mL in thefed state. The partition coefficient of the drug between the lipophilicmicrophase-forming material and aqueous solution is 4000. When excessdrug is dosed under these conditions, the total amount of drug dissolvedat equilibrium is calculated as in the table below:

Conc. Lipophilic Conc. Microphase- Free Drug in Drug in Total Bileforming Drug Bile Lipophilic Dissolved Fed/ Fed/Fasted Salts MaterialConc. Salts Microphases Drug Fasted State (Vol %) (mg/mL) (μgA/mL)(μgA/mL) (μgA/mL) (μgA/mL) Ratio Fasted 0.5 0 1.0 1.0 0 2.0 2.5 Fed 2.00 1.0 4.0 0 5.0 Fasted 0.5 1.0 1.0 1.0 4.0 6.0 1.2 Fed 2.0 0.5 1.0 4.02.0 7.0Thus, the use of a lipophilic microphase-forming material results in afed/fasted ratio that is closer to 1 than when such materials are notused. This equalization of the amount of drug present in highly labile,highly mobile species between the fed and fasted states can lead to amore uniform bioavailability between the fed and fasted states.

The foregoing and other objectives, features, and advantages of theinvention will be more readily understood upon consideration of thefollowing detailed description of the invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention provides in one aspect a composition comprising(1) a solid adsorbate comprising a low-solubility drug adsorbed to ahigh surface area substrate, and (2) a lipophilic microphase-formingmaterial. The lipophilic microphase-forming material may either bepresent on the adsorbate, may be mixed with the solid adsorbate, or maybe separate from but co-administered with the adsorbate. Thecompositions may optionally include a concentration-enhancing polymer.Suitable drugs, lipophilic microphase-forming materials, adsorbates,optional concentration-enhancing polymers, and methods for making thecompositions, are discussed in more detail below.

The Drug

The term “drug” is conventional, denoting a compound having beneficialprophylactic and/or therapeutic properties when administered to ananimal, especially humans. Preferably, the drug is a “low-solubilitydrug,” meaning that the drug has a minimum aqueous solubility atphysiologically relevant pH (e.g., pH 1-8) of about 0.5 mg/mL or less.The invention finds greater utility as the aqueous solubility of thedrug decreases. Thus, compositions of the present invention arepreferred for low-solubility drugs having an aqueous solubility of lessthan about 0.1 mg/mL, more preferred for low-solubility drugs having anaqueous solubility of less than about 0.05 mg/mL, and even morepreferred for low-solubility drugs having an aqueous solubility of lessthan 0.01 mg/mL. In general, it may be said that the drug has adose-to-aqueous solubility ratio greater than about 10 mL, and moretypically greater than about 100 mL, where the aqueous solubility(mg/mL) is the minimum value observed in any physiologically relevantaqueous solution (e.g., those with pH values between 1 and 8) includingUSP simulated gastric and intestinal buffers, and dose is in mg. Thus, adose-to-aqueous solubility ratio may be calculated by dividing the dose(in mg) by the aqueous solubility (in mg/mL).

The drug does not need to be a low-solubility drug in order to benefitfrom this invention, although low-solubility drugs represent a preferredclass for use with the invention. Even a drug that nonetheless exhibitsappreciable aqueous solubility in the desired environment of use canbenefit from the increased solubility/bioavailability made possible bythis invention if it reduces the size of the dose needed for therapeuticefficacy or increases the rate of drug absorption in cases where a rapidonset of the drug's effectiveness is desired. In such cases, the drugmay have an aqueous solubility up to about 1 to 2 mg/mL, or even as highas about 20 to 40 mg/mL.

In addition, the invention finds utility when the drug has a relativelyhigh absorption rate constant. By “absorption rate constant” is meant aconstant that describes the rate at which the drug is moved from thesite of administration (e.g., the GI tract of an animal) to theextra-cellular compartment of the body. Absorption rate constants aregenerally described by zero-order or first-order models. See forexample, Remington's The Science and Practice of Pharmacy, 20^(th) Ed(2000). The invention finds particular utility when the drug has anabsorption rate constant of at least 0.005 min⁻¹, more utility when thedrug has an absorption rate constant of at least 0.01 min⁻¹, and evenmore utility when the drug has an absorption rate constant of at least0.03 min⁻¹ or higher.

Preferred classes of drugs include, but are not limited to,antihypertensives, antianxiety agents, anticlotting agents,anticonvulsants, blood glucose-lowering agents, decongestants,antihistamines, antitussives, antineoplastics, beta blockers,anti-inflammatories, antipsychotic agents, cognitive enhancers,cholesterol-reducing agents, anti-atherosclerotic agents, antiobesityagents, autoimmune disorder agents, anti-impotence agents, antibacterialand antifungal agents, hypnotic agents, anti-Parkinsonism agents,anti-Alzheimer's disease agents, antibiotics, anti-depressants,antiviral agents, glycogen phosphorylase inhibitors, and cholesterylester transfer protein inhibitors.

Each named drug should be understood to include any pharmaceuticallyacceptable forms of the drug. By “pharmaceutically acceptable forms” ismeant any pharmaceutically acceptable derivative or variation, includingstereoisomers, stereoisomer mixtures, enantiomers, solvates, hydrates,isomorphs, polymorphs, neutral forms, salt forms and prodrugs. Specificexamples of antihypertensives include prazosin, nifedipine, amlodipinebesylate, trimazosin and doxazosin; specific examples of a bloodglucose-lowering agent are glipizide and chlorpropamide; a specificexample of an anti-impotence agent is sildenafil and sildenafil citrate;specific examples of antineoplastics include chlorambucil, lomustine andechinomycin; a specific example of an imidazole-type antineoplastic istubulazole; a specific example of an anti-hypercholesterolemic isatorvastatin calcium; specific examples of anxiolytics includehydroxyzine hydrochloride and doxepin hydrochloride; specific examplesof anti-inflammatory agents include betamethasone, prednisolone,aspirin, piroxicam, valdecoxib, carprofen, celecoxib, flurbiprofen and(+)-N-{4-[3-(4-fluorophenoxy)phenoxy]-2-cyclopenten-1-yl}-N-hyroxyurea;a specific example of a barbiturate is phenobarbital; specific examplesof antivirals include acyclovir, nelfinavir, and virazole; specificexamples of vitamins/nutritional agents include retinol and vitamin E;specific examples of beta blockers include timolol and nadolol; aspecific example of an emetic is apomorphine; specific examples of adiuretic include chlorthalidone and spironolactone; a specific exampleof an anticoagulant is dicumarol; specific examples of cardiotonicsinclude digoxin and digitoxin; specific examples of androgens include17-methyltestosterone and testosterone; a specific example of a mineralcorticoid is desoxycorticosterone; a specific example of a steroidalhypnotic/anesthetic is alfaxalone; specific examples of anabolic agentsinclude fluoxymesterone and methanstenolone; specific examples ofantidepression agents include sulpiride,[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-(1-ethylpropyl)-amine,3,5-dimethyl-4-(3′-pentoxy)-2-(2′,4′,6′-trimethylphenoxy)pyridine,pyroxidine, fluoxetine, paroxetine, venlafaxine and sertraline; specificexamples of antibiotics include carbenicillin indanyl-sodium,bacampicillin hydrochloride, troleandomycin, doxycyline hyclate,ampicillin and penicillin G; specific examples of anti-infectivesinclude benzalkonium chloride and chlorhexidine; specific examples ofcoronary vasodilators include nitroglycerin and mioflazine; a specificexample of a hypnotic is etomidate; specific examples of carbonicanhydrase inhibitors include acetazolamide and chlorzolamide; specificexamples of antifungals include econazole, terconazole, fluconazole,voriconazole, and griseofulvin; a specific example of an antiprotozoalis metronidazole; specific examples of anthelmintic agents includethiabendazole and oxfendazole and morantel; specific examples ofantihistamines include astemizole, levocabastine, cetirizine,decarboethoxyloratadine and cinnarizine; specific examples ofantipsychotics include ziprasidone, olanzepine, thiothixenehydrochloride, fluspirilene, risperidone and penfluridole; specificexamples of gastrointestinal agents include loperamide and cisapride;specific examples of serotonin antagonists include ketanserin andmianserin; a specific example of an anesthetic is lidocaine; a specificexample of a hypoglycemic agent is acetohexamide; a specific example ofan anti-emetic is dimenhydrinate; a specific example of an antibacterialis cotrimoxazole; a specific example of a dopaminergic agent is L-DOPA;specific examples of anti-Alzheimer's Disease agents are THA anddonepezil; a specific example of an anti-ulcer agent/H2 antagonist isfamotidine; specific examples of sedative/hypnotic agents includechlordiazepoxide and triazolam; a specific example of a vasodilator isalprostadil; a specific example of a platelet inhibitor is prostacyclin;specific examples of ACE inhibitor/antihypertensive agents includeenalaprilic acid and lisinopril; specific examples of tetracyclineantibiotics include oxytetracycline and minocycline; specific examplesof macrolide antibiotics include erythromycin, clarithromycin, andspiramycin; a specific example of an azalide antibiotic is azithromycin;specific examples of glycogen phosphorylase inhibitors include[R-(R′S′)]-5-chloro-N-[2-hydroxy-3-{methoxymethylamino}-3-oxo-1-(phenylmethyl)propyl-1H-indole-2-carboxamide and 5-chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-(2R)-hydroxy-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl-)-3-oxypropyl]amide;and specific examples of cholesteryl ester transfer protein (CETP)Inhibitors include [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester, [2R,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester, [2R, 4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester,(2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol, the drugs disclosed in commonly owned U.S. patentapplication Ser. Nos. 09/918,127 and 10/066,091, both of which areincorporated herein by reference in their entireties for all purposes,and the drugs disclosed in the following patents and publishedapplications: DE 19741400 A1; DE 19741399A1; WO 9914215 A1; WO 9914174;DE19709125 A1; DE 19704244 A1; DE 19704243 A1; EP 818448 A1; WO 9804528A2; DE 19627431 A1; DE 19627430 A1; DE 19627419 A1; EP 796846 A1;DE19832159; DE 818197; DE 19741051; WO 9941237 A1; WO 9914204 A1; WO9835937 A1; JP 11049743; WO 200018721; WO 200018723; WO 200018724; WO200017164; WO 200017165; WO 200017166; EP 992496; and EP 987251, all ofwhich are hereby incorporated by reference in their entireties for allpurposes.

In a preferred embodiment, the drug is a lipophilic drug. The inventorshave recognized this subclass of drugs that are essentially aqueousinsoluble, highly hydrophobic, and are characterized by a set ofphysical properties. This subclass exhibits dramatic enhancements inaqueous concentration and bioavailability when formulated ascompositions of the present invention.

The first property of this subclass of essentially insoluble,hydrophobic drugs is extremely low aqueous solubility. By “extremely lowaqueous solubility” is meant that the minimum aqueous solubility atphysiologically relevant pH (pH of 1 to 8) is less than about 10 μg/mland preferably less than about 1 μg/ml.

A second property is a very high dose-to-solubility ratio. Extremely lowaqueous solubility often leads to poor or slow absorption of the drugfrom the fluid of the gastrointestinal tract, when the drug is dosedorally in a conventional manner. For extremely low solubility drugs,poor absorption generally becomes progressively more difficult as thedose (mass of drug given orally) increases. Thus, a second property ofthis subclass of essentially insoluble, hydrophobic drugs is a very highdose (in mg) to aqueous solubility (in mg/ml) ratio (ml). By “very highdose-to-aqueous solubility ratio” is meant that the dose-to-aqueoussolubility ratio has a value of at least 1000 ml, and preferably atleast 5,000 ml, and more preferably at least 10,000 ml.

A third property of this subclass of essentially insoluble, hydrophobicdrugs is that they are extremely hydrophobic. By extremely hydrophobicis meant that the Log P value of the drug, has a value of at least 4.0,preferably a value of at least 5.0, and more preferably a value of atleast 5.5. Log P, defined as the base 10 logarithm of the ratio of thedrug solubility in octanol to the drug solubility in water, is a widelyaccepted measure of hydrophobicity. Log P may be measured experimentallyor calculated using methods known in the art. Calculated Log P valuesare often referred to by the calculation method, such as Clog P, Alog Pand Mlog P.

Primarily, as a consequence of some or all of these properties, drugs ofthis subclass typically have very low absolute bioavailabilities.Specifically, the absolute bioavailability of drugs in this subclasswhen dosed orally in their undispersed state is typically less thanabout 10% and more often less than about 5%.

Lipophilic Microphase-Forming Materials

The lipophilic microphase-forming material may comprise a surfactantand/or a lipophilic material. Thus, as used herein, the “lipophilicmicrophase-forming material” is intended to include a single material aswell as two or more materials. The lipophilic microphase-formingmaterial must (1) be water immiscible (2) be capable of forming aplurality of small lipophilic microphases in the use environment and (3)have a relatively high partition coefficient for the drug in the useenvironment.

The lipophilic microphase-forming material must be “water immiscible,”meaning that the material when administered as prescribed herein to anin vivo aqueous use environment exceeds its solubility as solvatedmolecules thus requiring the formation of a second phase. Ideally such asecond phase takes the form of a large number of small phases such asmicelles or a microemulsion. In many cases the lipophilicmicrophase-forming material has a critical micelle concentration(“CMC”), defined as the aqueous concentration above which micelles form.In such cases, the lipophilic microphase-forming material is present ata concentration above the CMC, thus leading to the formation ofmicelles. The lipophilic microphase is a separate phase in the aqueoususe environment; the separate phase ranging from extremely smallaggregates such as micelles or as large droplets up to a few microns insize. The lipophilic microphase-forming material also is capable offorming a plurality of small lipophilic microphases in an in vivoaqueous use environment without the need for stirring, agitation orother mechanical energy. The material need not be self-emulsifying.Nevertheless, preferably the lipophilic microphase-forming materialshould not agglomerate into a single phase within the use environment,but should remain as a plurality of microphases for at least 1 hour andpreferably longer. When the composition is administered to an in vitroaqueous use environment, the lipophilic microphase-forming materialshould form a plurality of microphases with at most only slightagitation of the use environment. The microphases remain small for atleast 1 hour, and more preferably at least 4 hours, after administrationto the use environment.

It should be noted that some lipophilic materials that do not form aplurality of microphases when administered alone may often form suchphases when administered with the drug/substrate adsorbate and optionalconcentration-enhancing polymer.

The resulting lipophilic microphases formed in the aqueous useenvironment are preferably small. By “small” is meant that thelipophilic microphase-forming material forms lipophilic microphases thatare generally less than about 100 μm in characteristic diameter. By“characteristic diameter” is meant the volume average diameter of themicrophase in the use environment. The characteristic diameter may bedetermined by standard measurement techniques, such as dynamic lightscattering and static light scattering, or by examination via optical-or scanning-election microscopy, transmission-electron microscopy,coulter-counting methods, and size-exclusion field-flow fractionation.The resulting particles may be smaller, such as less than about 10 μm incharacteristic diameter, less than about 1 μm in characteristicdiameter, less than about 100 nm in characteristic diameter, and lessthan about 50 nm in characteristic diameter. In some instances, aportion of the lipophilic microphase-forming material may form smallmicrophases, with the remaining material being present as largermicrophases. When there is such a distribution in sizes, it is preferredthat at least a substantial portion of the lipophilic microphase-formingmaterial be present in small microphases. By “substantial portion” ismeant that about 10 vol % or more of the material is present in smallmicrophases. Preferably about 15 vol % or more, more preferably about 20vol % or more of the material is present in small microphases.

The size of the microphases depends on the other components of thecomposition, such as the drug and polymer, the manner in which thecomponents of the composition are combined, (such as having thelipophilic microphase-forming material adsorbed to the drug/substrateadsorbate), as well as the components of the use environment. This isparticularly true in an in vivo use environment where the presence ofproteins, bile salts, and other surface-active agents may cause somecompositions to form suitably small lipophilic microphases even thoughthey do not form such microphases in in vitro tests. In addition, it iswell known that, in the in vivo environment, many lipophilicmicrophase-forming materials such as mono-, di-, and triglycerides mayundergo chemical conversion to other species that in time form themicrophases. Thus the ultimate test of an appropriate lipophilicmicrophase-forming material and composition is best conducted in the invivo use environment.

The lability of a drug from the free drug phase into and out of thelipophilic microphase is generally a function of the microphase size. By“lability” is meant the kinetics or rate of drug release or drugpartitioning into or out of the microphase. Generally, for a given massof lipophilic microphase-forming material, lability increases as thesize of the microphase decreases. As the aqueous solubility of the drugdecreases, it is preferable for the characteristic size of themicrophase to be smaller. Thus, when the aqueous solubility of the drugis extremely low, such as about 1 μg/ml or less, preferred compositionsgenerally form microphases less than about 1 μm in characteristicdiameter when dosed to the in vivo use environment.

The microphases may also increase the rate of drug absorption in the GItract. Without wishing to be bound by any theory or mechanism of action,it is believed that the microphases can increase the transport rate ofthe drug through the unstirred water layer adjacent to the intestinalwall. As described below, the drug has a high partition coefficient inthe lipophilic microphase-forming material, resulting in a highconcentration of drug in the microphases. Thus, when the microphases aretransported across the unstirred water layer, a large amount of drug istransported as well. Generally, the smaller the size of the microphases,the higher the rate of transport across the unstirred water layer. Oncetransported through the unstirred water layer, the high lability of drugin the lipophilic microphase-forming material allows the concentrationof free drug at the intestinal wall to be maintained at a higherconcentration than if the lipophilic microphase-forming material was notpresent. As a result, absorption is increased.

The drug should also have a relatively high partition coefficient in thelipophilic microphase-forming material. By partition coefficient ismeant the ratio of the concentration of drug present in the lipophilicmicrophases to the free drug concentration as follows:

$\begin{matrix}{K_{p} = \frac{\lbrack{Drug}\rbrack_{lipophile}}{\lbrack{Drug}\rbrack_{free}}} & (I)\end{matrix}$where K_(p) is the partition coefficient, [Drug]_(lipophile) is theconcentration of the drug in the lipophilic microphases, and[Drug]_(free) is the free drug concentration.

In a given volume of the aqueous use environment, the total amount ofdrug in the lipophilic microphases is also dependent on the amount oflipophilic microphase present. Thus the concentration of drug in thelipophilic microphase per unit volume of the aqueous use environment,[Drug]_(aqueous,lipophile), is given by:[Drug]_(aqueous,lipophile)=X_(lipophile)·K_(p)·[Drug]_(free)where X_(lipophile) is the volume fraction of the lipophilic microphasein the use environment.

In situations where the drug is only present as free drug and drugwithin the lipophilic microphase, the total dissolved drug concentration[Drug]_(aqueous,total) is given by:[D]_(aqueous,total)=[Drug]_(free)+[Drug]_(aqueous,lipophile)   (II)[Drug]_(aqueous,total)=[Drug]_(free)·[1+X_(lipophile)·K_(p)]

In order for the presence of the lipophile to have a large impact on thebioavailability of a composition, there generally must be a significantfraction of the total drug dosed that is within the lipophilicmicrophase. By significant fraction it is generally meant that at leastabout 0.1% and preferably at least about 1% of the total drug dosed ispresent in the use environment within the lipophilic microphase-formingmaterial. According to the above equations, the fraction of the totaldrug present within the lipophilic microphases generally increases with:(1) increasing K_(p), (2) increasing X_(lipophile), and (3) increasing[Drug]_(free).

Since there are practical limits to the size of oral dosage forms thatmay be administered, it is generally undesirable to have large values ofX_(lipophile). For example, when the compositions of the presentinvention are formed into an oral tablet or capsule for administration,the mass of the tablet or capsule is generally less than about 1000 mgand preferably less than about 700 mg. Since a significant portion ofthe dosage form must also comprise the active drug and other excipients,the maximum amount of lipophilic microphase-forming material in a singleoral dosage form is about 500 mg. When dosed orally to the GI tract of ahuman, the aqueous volume into which the lipophilic microphase-formingmaterial composition disperses is generally about 50 ml up to about 500ml, depending on the fed state of the subject. Thus, the maximumpractical value for X_(lipophile) is about 0.001 to 0.01. Thus, forexample, when the dose of the drug is 100 mg, it is desirable to have atleast 0.1 wt % (0.1 mg) and preferably at least 1 wt % (1 mg) of thedrug be present in the lipophilic microphase-forming material. Thisgenerally means that the concentration of drug in the lipophilicmicrophase-forming material (in wt %) when the composition is dosedorally to a human is at least about 0.1 mg/500 mg or 0.02 wt % andpreferably at least about 0.2 wt % (1 mg/500 mg).

The drug should have a relatively high partition coefficient in thelipophilic microphase-forming material. Preferably, the partitioncoefficient is about 10 or more, more preferably about 50 or more, evenmore preferably about 100 or more, and most preferably about 500 ormore. Generally, the lower the aqueous solubility of a drug, the higherthe partition coefficient should be to have a large impact onbioavailability. Thus, the partition coefficient may be greater thanabout 1000, greater than about 5000, greater than about 10,000, and insome cases greater than about 50,000 or more. For drugs with very lowaqueous solubilities, the partition coefficient may be greater thanabout 100,000 or even greater than about 1,000,000 or more.

In one aspect, the minimum K_(p) may be determined by determining theK_(p) necessary to achieve the desired concentration of drug in thelipophilic microphase forming material. Since the concentration of drugin the lipophilic microphase-forming material at equilibrium is givenby:[Drug]_(lipophile)=[Drug]_(free)·K_(p)then the minimum K_(p) may be determined by setting the free drugconcentration, [Drug]_(free), to the aqueous solubility of the drug,S_(xtal). The aqueous solubility, S_(xtal), is the aqueous solubility ofthe thermodynamically most stable crystalline form of the drug, or theunadsorbed amorphous form if the crystalline form is unknown, over thepH range of 6 to 8. Using the desired concentration of drug in thelipophilic microphase-forming material given above, then the minimumK_(p) should generally be at least about 0.02/S_(xtal), where S_(xtal)is measured in wt %. Preferably, K_(p) is greater than about0.2/S_(xtal), more preferably greater than about 0.5/S_(xtal), even morepreferably greater than about 1/S_(xtal), and most preferably greaterthan about 2/S_(xtal). Thus, when the aqueous solubility of the drug inthe pH range of 6 to 8 is about 10 μg/ml or about 0.001 wt %, then K_(p)should be greater than about 20 (0.02 wt %/0.001 wt %), preferablygreater than about 200 (0.2 wt %/0.001 wt %), more preferably greaterthan about 500 (0.5 wt %/0.001 wt %), even more preferably greater than1000 (1 wt %/0.001 wt %), and most preferably greater than 2000 (2 wt%/0.001 wt %).

Generally, it is preferred that the lower the mass of lipophilicmicrophase-forming material in the composition, the higher the partitioncoefficient so as to have a large impact on bioavailability. In oneaspect, it is preferred that the compositions satisfy the followingequation:M_(lipophile)*K_(p)≥5,where M_(lipophile) is the mass of lipophile in the composition ingrams. Preferably, M_(lipophile)*K_(p)≥10, more preferablyM_(lipophile)*K_(p)≥50, and most preferably M_(lipophile)*K_(p)≥100. Forexample, as discussed above, the maximum amount of lipophilicmicrophase-forming material in a single oral dosage form is about 500mg, or 0.5 gm. Thus, a composition containing 0.5 gm of a lipophilicmicrophase-forming material should have a partition coefficient of 10 ormore, preferably 20 or more, more preferably 100 or more, and mostpreferably 200 or more.

The partition coefficient K_(p) for a drug in a particular lipophilicmicrophase-forming material may be determined by any method or series ofexperiments in which the concentration of drug present as free drug anddrug present in lipophilic microphases can be determined. One exemplarymethod is as follows. Crystalline drug (or amorphous drug if thecrystalline form of the drug is not known) is added to an appropriatebuffer solution such as phosphate buffered saline (PBS) (describedbelow) at an amount such that if all of the drug dissolved theconcentration would be greater than the equilibrium aqueous solubilityof the drug. The concentration of free drug in the solution is thendetermined by any technique that can quantitatively measure the amountof dissolved drug in solution, such as high-performance liquidchromatography (HPLC) or nuclear magnetic resonance (NMR) spectroscopy.Typically, this is accomplished by collecting a sample of the solutioncontaining the drug and either filtering or centrifuging the sample toremove undissolved drug species, and then analyzing the concentration ofthe remaining dissolved drug. This technique provides the value of[Drug]_(free) in Equation I. Next, crystalline drug is added to anappropriate buffer solution to which various amounts of the lipophilicmicrophase-forming material had been added, such as 1 vol %, 2 vol % and3 vol %, again at an amount such that if all of the drug dissolved theconcentration of drug either present as free drug or in the lipophilicmicrophase would be greater than the equilibrium aqueous solubility ofthe drug with the lipophilic microphase-forming material present. Thetotal concentration of total dissolved drug, that is the sum of drugpresent as free drug plus drug present in lipophilic microphases, (asgiven in Equation II)—is determined using the same techniques describedabove. The total dissolved drug concentration [Drug]_(aqueous,total) isthen plotted versus the vol % lipophilic microphase-forming material inthe solution. The slope of the line for this graph is equal to theproduct of the free drug concentration (which is normally assumed to beequal to the aqueous solubility of the drug in the absence of thelipophilic microphase-forming material, or S_(xtal)) and K_(p). Thus,K_(p)=slope/S_(xtal). When the aqueous solubility of the lipophilicmicrophase-forming material or the “critical micelle concentration”(CMC) of the lipophilic microphase-forming material is very smallrelative to the amount of lipophilic microphase-forming material used inthe above experiment, the y-intercept of the line through the datapoints is approximately equal to the crystalline drug aqueoussolubility, S_(xtal). When the amount of lipophilic microphase-formingmaterial used is only slightly larger than the CMC or the lipophilicmicrophase-forming material aqueous solubility, then the values ofX_(lipophile) should be corrected by subtracting the CMC or solubilityfrom the total volume fraction of lipophilic microphase-forming materialadded to the solution.

In one embodiment of this invention, the lipophilic microphase-formingmaterial is part of the drug/substrate adsorbate. In such cases, it ispreferred that the adsorbate comprise no greater than 50 wt % lipophilicmicrophase-forming material, preferably no greater than 40 wt %, morepreferably no greater than 30 wt %.

Another embodiment of the present invention is a solid oral dosage formcomprising the novel compositions. The solid dosage form may take theform of one or more tablets or capsules or a multiplicity of particlesor granules. When the solid dosage form is one or more tablets orcapsules, the dosage form may be taken orally by swallowing whole,chewed and then swallowed, or the dosage form may disintegrate andoptionally dissolve in the mouth and then be swallowed. When the soliddosage form is a multiplicity of small particles or granules the powderor granules may be ingested by any known method, including firstdispersing in an aqueous vehicle and then swallowing, or mixing withfood and then ingesting along with the food.

In order for the compositions of the present invention to be efficientlyformed into solid dosage forms it is generally desirable for thelipophilic microphase-forming materials to have relatively high meltingpoints and relatively high T_(g) values. However, even lipophilicmicrophase-forming materials that are liquid at room temperature may beformed into solid dosage forms as long as the amount incorporated intothe dosage form is not too high.

When the lipophilic microphase-forming material is either a liquid atroom temperature or becomes liquid at a temperature of about 50° C. orless, a preferred embodiment is to disperse the lipophilicmicrophase-forming material in a solid excipient. The lipophilicmicrophase-forming material may be adsorbed to the surface of a solidmaterial such as microcrystalline cellulose; silica; dibasic calciumphosphate; calcium silicate (Zeodor™); clays, such as kaolin (hydratedaluminum silicate), bentonite (hydrated aluminum silicate), hectoriteand Veegum®; Na-, Al-, and Fe-montmorillonite; silicon dioxide(Cab-O-Sil® or Aerosil®); magnesium trisilicate; aluminum hydroxide;magnesium hydroxide, magnesium oxide or talc. Highly porous materialssuch as calcium silicate are preferred. This embodiment has theadvantage of separating the lipophilic microphase-forming material fromthe drug/substrate adsorbate, thus minimizing the effect of thelipophilic microphase-forming material on the stability of theadsorbate.

Alternatively, the lipophilic microphase-forming material may bedispersed in a water soluble or water dispersible polymer, as either aseparate phase, or homogeneously distributed throughout the polymer. Inone preferred embodiment, the lipophilic microphase-forming material isdispersed in a concentration-enhancing polymer. Such lipophilicmicrophase-forming material dispersions serve to (1) render thelipophilic microphase-forming material solid to aid in incorporationinto solid dosage forms, (2) aid in dispersing of the lipophilicmicrophase-forming material as a microphase, and (3) provideconcentration-enhancing polymer for generating and sustaining highconcentrations of dissolved drug. In an often particularly preferredembodiment, the lipophilic microphase-forming material is adsorbed,along with the drug, to a high surface area substrate. Such lipophilicmicrophase-forming material adsorbates are often preferred even when thelipophilic microphase-forming material is a solid below about 50° C.

The lipophilic microphase-forming material may be either hydrophobic,amphiphilic, or a mixture of a hydrophobic and an amphiphilic material.By “amphiphilic” material is meant a material that has both hydrophobicand hydrophilic portions. Since hydrophobic materials alone tend not toform small microphases in an aqueous use environment, amphiphilic andmixtures of amphiphilic and hydrophobic materials are preferred.However, it is known that some such hydrophobic materials will formmicrophases due to the influence of (1) other excipients such as theconcentration-enhancing polymer, (2) the drug itself, or (3) naturallyoccurring components of the GI tract. Thus, hydrophobic materials aloneform a part of the invention as long as they form suitably smallmicrophases when the compositions or dosage forms are administered to ause environment. The use of a mixture of hydrophobic and amphiphilicmaterial may be preferred because the hydrophobic material oftenprovides a higher partition coefficient, while the amphiphilic materialmay limit or reduce the size of the lipophilic microphases in the useenvironment. Thus, such mixtures may have higher lability and higherpartition coefficients.

Generally, the lipophilic microphase-forming materials have a molecularweight of less than about 20,000 daltons. However, most lipophilicmicrophase-forming materials have molecular weights below about 2,000daltons. Additionally, the lipophilic microphase-forming materials arewater immiscible and form lipophilic microphases. The lipophilicmicrophase-forming material is therefore distinct from theconcentration-enhancing polymer. The concentration-enhancing polymersgenerally have molecular weights of greater than about 10,000 daltons,are more soluble or dispersible in the use environment, and aregenerally less hydrophobic.

Examples of amphiphilic materials suitable for use as the lipophilicmicrophase-forming material include: sulfonated hydrocarbons and theirsalts, such as sodium 1,4-bis(2-ethylhexyl) sulfosuccinate, also knownas docusate sodium (CROPOL) and sodium lauryl sulfate (SLS);polyoxyethylene alkyl ethers (CREMOPHOR A, BRIJ); polyoxyethylenesorbitan fatty acid esters (polysorbates, TWEEN); short-chain glycerylmono-alkylates (HODAG, IMWITOR, MYRJ); polyglycolized glycerides(GELUCIREs); mono- and di-alkylate esters of polyols, such as glycerol;nonionic surfactants such as polyoxyethylene 20 sorbitan monooleate,(polysorbate 80, sold under the trademark TWEEN 80, availablecommercially from ICI); polyoxyethylene 20 sorbitan monolaurate(Polysorbate 20, TWEEN 20); polyoxyethylene (40 or 60) hydrogenatedcastor oil (available under the trademarks CREMOPHOR® RH40 and RH60 fromBASF); polyoxyethylene (35) castor oil (CREMOPHOR® EL); polyethylene(60) hydrogenated castor oil (Nikkol HCO-60); alpha tocopherylpolyethylene glycol 1000 succinate (Vitamin E TPGS); glyceryl PEG 8caprylate/caprate (available commercially under the registered trademarkLABRASOL® from Gattefosse); PEG 32 glyceryl laurate (sold commerciallyunder the registered trademark GELUCIRE 44/14 by Gattefosse),polyoxyethylene fatty acid esters (available commercially under theregistered trademark MYRJ from ICI), polyoxyethylene fatty acid ethers(available commercially under the registered trademark BRIJ from ICI).Alkylate esters of polyols may be considered amphiphilic or hydrophobicdepending on the number of alkylates per molecule and the number ofcarbons in the alkylate. When the polyol is glycerol, mono- anddi-alkylates are often considered amphiphilic while trialkylates ofglycerol are generally considered hydrophobic. However, some scientistsclassify even medium chain mono- and di-glycerides as hydrophobic. Seefor example Patel et al U.S. Pat. No. 6,294,192 (B1), which isincorporated herein in its entirety by reference. Regardless of theclassification, compositions comprising mono- and di-glycerides arepreferred compositions of this invention. Other suitable amphiphilicmaterials may be found in Patel, U.S. Pat. No. 6,294,192 and are listedas “hydrophobic non-ionic surfactants and hydrophilic ionicsurfactants.”

It should be noted that some amphiphilic materials may not be waterimmiscible by themselves, but instead are at least somewhat watersoluble. Such amphiphilic materials may nevertheless be used in mixturesto form the lipophilic microphase, particularly when used as mixtureswith hydrophobic materials.

Examples of hydrophobic materials suitable for use as the lipophilicmicrophase-forming material include: medium-chain glyceryl mono-, di-,and tri-alkylates (CAPMUL MCM, MIGLYOL 810, MYVEROL 18-92, ARLACEL 186,fractionated coconut oil, light vegetable oils); sorbitan esters(ARLACEL 20, ARLACEL 40); long-chain fatty alcohols (stearyl alcohol,cetyl alcohol, cetostearyl alcohol); long-chain fatty-acids (stearicacid); and phospholipids (egg lecithin, soybean lecithin, vegetablelecithin, and 1,2-diacyl-sn-glycero-3-phosphocholine, such as1-palmitoyl-2-oleyl-sn-glycero-3-phosphocoline,1,2-dipalmitoyl-sn-glycero-3-phosphocholine,1,2-distearoyl-sn-glycero-3-phosphocholine,1-plamitoyl-2-stearoyl-sn-glycero-3-phosphocholine, and other natural orsynthetic phosphatidyl cholines); mono and diglycerides of capric andcaprylic acid under the following registered trademarks: Capmul® MCM,MCM 8, and MCM 10, available commercially from Abitec, and Imwitor® 988,742 or 308, available commercially from Condea Vista; polyoxyethylene 6apricot kernel oil, available under the registered trademark Labrafil® M1944 CS from Gattefosse; polyoxyethylene corn oil, availablecommercially as Labrafil® M 2125; propylene glycol monolaurate,available commercially as Lauroglycol from Gattefosse; propylene glycoldicaprylate/caprate available commercially as Captex® 200 from Abitec orMiglyol® 840 from Condea Vista, polyglyceryl oleate availablecommercially as Plurol oleique from Gattefosse, sorbitan esters of fattyacids (e.g., Span® 20, Crill® 1, Crill® 4, available commercially fromICI and Croda), and glyceryl monooleate (Maisine, Peceol); medium chaintriglycerides (MCT, C6-C12) and long chain triglycerides (LCT, C14-C20)and mixtures of mono-, di-, and triglycerides, or lipophilic derivativesof fatty acids such as esters with alkyl alcohols; fractionated coconutoils, such as Miglyol® 812 which is a 56% caprylic (C8) and 36% capric(C10) triglyceride, Miglyol® 810 (68% C8 and 28% C10), Neobee® M5,Captex® 300, Captex® 355, and Crodamol® GTCC; (Miglyols are supplied byCondea Vista Inc. (Huls), Neobee® by Stepan Europe, Voreppe, France,Captex by Abitec Corp., and Crodamol by Croda Corp); vegetable oils suchas soybean, safflower, corn, olive, cottonseed, arachis, sunflower seed,palm, or rapeseed; fatty acid esters of alkyl alcohols such as ethyloleate and glyceryl monooleate. Other hydrophobic materials suitable foruse as the lipophilic microphase-forming material include those listedin Patel, U.S. Pat. No. 6,294,192 as “hydrophobic surfactants.”Exemplary classes of hydrophobic materials include: fatty alcohols;polyoxyethylene alkylethers; fatty acids; glycerol fatty acidmonoesters; glycerol fatty acid diesters; acetylated glycerol fatty acidmonoesters; acetylated glycerol fatty acid diesters, lower alcohol fattyacid esters; polyethylene glycol fatty acid esters; polyethylene glycolglycerol fatty acid esters; polypropylene glycol fatty acid esters;polyoxyethylene glycerides; lactic acid derivatives of monoglycerides;lactic acid derivatives of diglycerides; propylene glycol diglycerides;sorbitan fatty acid esters; polyoxyethylene sorbitan fatty acid esters;polyoxyethylene-polyoxypropylene block copolymers; transesterifiedvegetable oils; sterols; sterol derivatives; sugar esters; sugar ethers;sucroglycerides; polyoxyethylene vegetable oils; polyoxyethylenehydrogenated vegetable oils; reaction products of polyols and at leastone member of the group consisting of fatty acids, glycerides, vegetableoils, hydrogenated vegetable oils, and sterols; and mixtures thereof.Mixtures of relatively hydrophilic materials, such as those termedherein as “amphiphilic” or in Patel as “hydrophilic surfactants” and theabove hydrophobic materials are particularly suitable. Specifically, themixtures of hydrophobic surfactants and hydrophilic surfactantsdisclosed by Patel are suitable and for many compositions, preferred.However, unlike Patel, mixtures that include triglycerides as ahydrophobic component are also suitable.

In one embodiment, the lipophilic microphase-forming material isselected from the group consisting of polyglycolized glycerides(GELUCIREs); polyoxyethylene (40 or 60) hydrogenated castor oil(available under the trademarks CREMOPHOR® RH40 and RH60 from BASF);polyoxyethylene (35) castor oil (CREMOPHOR® EL); polyethylene (60)hydrogenated castor oil (Nikkol HCO-60); alpha tocopheryl polyethyleneglycol 1000 succinate (Vitamin E TPGS); glyceryl PEG 8 caprylate/caprate(available commercially under the registered trademark LABRASOL® fromGattefosse); PEG 32 glyceryl laurate (sold commercially under theregistered trademark GELUCIRE 44/14 by Gattefosse); polyoxyethylenefatty acid esters (available commercially under the registered trademarkMYRJ from ICI); polyoxyethylene fatty acid ethers (availablecommercially under the registered trademark BRIJ from ICI);polyoxyethylene alkyl ethers (CREMOPHOR A, BRIJ); long-chain fattyalcohols (stearyl alcohol, cetyl alcohol, cetostearyl alcohol);long-chain fatty-acids (stearic acid); polyoxyethylene 6 apricot kerneloil, available under the registered trademark Labrafil® M 1944 CS fromGattefosse; polyoxyethylene corn oil, available commercially asLabrafil® M 2125; propylene glycol monolaurate, available commerciallyas Lauroglycol from Gattefosse; polyglyceryl oleate availablecommercially as Plurol oleique from Gattefosse; triglycerides, includingmedium chain triglycerides (MCT, C₆-C₁₂) and long chain triglycerides(LCT, C₁₄-C₂₀); fractionated coconut oils, such as Miglyol® 812 which isa 56% caprylic (C₈ ) and 36% capric (C₁₀) triglyceride, Miglyol® 810(68% C₈ and 28% C₁₀), Neobee® M5, Captex® 300, Captex® 355, andCrodamol® GTCC; (Miglyols are supplied by Condea Vista Inc. [Huls],Neobee® by Stepan Europe, Voreppe, France, Captex by Abitec Corp., andCrodamol by Croda Corp); vegetable oils such as soybean, safflower,corn, olive, cottonseed, arachis, sunflower seed, palm, or rapeseed;polyoxyethylene alkylethers; fatty acids; lower alcohol fatty acidesters; polyethylene glycol fatty acid esters; polyethylene glycolglycerol fatty acid esters; polypropylene glycol fatty acid esters;polyoxyethylene glycerides; lactic acid derivatives of monoglycerides;lactic acid derivatives of diglycerides; propylene glycol diglycerides;transesterified vegetable oils; sterols; sterol derivatives; sugaresters; sugar ethers; sucroglycerides; polyoxyethylene vegetable oils;polyoxyethylene hydrogenated vegetable oils; reaction products ofpolyols and at least one member of the group consisting of fatty acids,glycerides, vegetable oils, hydrogenated vegetable oils, and sterols;and mixtures thereof.

Especially preferred lipophilic microphase-forming materials includemixtures of polyethoxylated castor oils and medium-chain glyceryl mono-,di-, and/or tri-alkylates, (such as mixtures of CREMOPHOR RH40 andCAPMUL MCM), mixtures of polyoxyethylene sorbitan fatty acid esters andmedium-chain glyceryl mono-, di-, and/or tri-alkylates, (such asmixtures of TWEEN 80 and CAPMUL MCM), mixtures of polyethoxylated castoroils and medium-chain glyceryl mono-, di-, and/or tri-alkylates, (suchas mixtures of CREMOPHOR RH40 and ARLACEL 20), mixtures of sodiumtaurocholic acid and palmitoyl-2-oleyl-sn-glycero-3-phosphocholine andother natural or synthetic phosphatidylcholines, and mixtures ofpolyglycolized glycerides and medium-chain glyceryl mono-, di-, and/ortri-alkylates, (such as mixtures of Gelucire 44/14 and CAPMUL MCM).

The lipophilic microphase-forming material is present in a sufficientamount so that the combination of the drug/substrate adsorbate andlipophilic microphase-forming material provides concentrationenhancement, as described more fully below. In general, the lipophilicmicrophase-forming material is either present in the composition orco-administered with the drug/substrate adsorbate such that the weightratio of the lipophilic microphase-forming material to drug (hereinafterreferred to as the lipophile:drug ratio) ranges from about 0.05 to about500 (wt/wt). For solid dosage forms, the lipophile:drug ratio typicallyranges from about 0.1 to about 100, and more typically from 0.2 to 50.

The optimum amount of the lipophilic microphase-forming material dependson the mass of the dose of the drug, the partition coefficient, and theaqueous solubility of the drug. The optimum mass of the lipophilicmicrophase-forming material increases as the mass of the dose increases.The optimum mass of the lipophilic microphase-forming material decreasesas the partition coefficient increases and as the aqueous solubilityincreases.

Nevertheless, in general, the amount of lipophilic microphase formingmaterial present in the composition should not be so high that theconcentration of free drug obtained in the use environment is much lowerthan that obtained when less lipophilic microphase-forming material iscombined with the drug/substrate adsorbate and is introduced to the useenvironment. Generally, when the amount of lipophilic microphase-formingmaterial that is added to the composition is greater than the amountsuch that all of the drug introduced to the use environment is eitherpresent as free drug or is in the lipophilic microphases, then theperformance, in terms of improving drug absorption, will be reducedrelative to lower levels of the lipophilic microphase-forming material.Thus, it is preferred for compositions to contain less than this“maximum preferred level.” Nonetheless, levels of lipophilicmicrophase-forming material somewhat above this level may still improvedrug absorption relative to the adsorbate alone. This maximum preferredlevel will depend on the free drug concentration ([Drug]_(free),typically given in mg/ml), the density of the lipophilicmicrophase-forming material (ρ_(lipophile), typically given in mg/ml),and the partition coefficient (K_(p)). The maximum preferredlipophile:drug ratio is given by the following equation:Maximum lipophile:drug ratio=ρ_(lipophile)/(K_(p)·[Drug]_(free))It should be noted that for some values of K_(p) and [Drug]_(free), themaximum preferred lipophile:drug ratio will be quite large. For example,when ρ_(lipophile)=1000 mg/mL, K_(p)=100, and [Drug]_(free)=0.001 mg/mL,the maximum preferred lipophile:drug ratio is calculated to be 10,000.If the drug dose is, for example 100 mg, this results in a maximumpreferred lipophile dose of 1000 g. Such high doses of lipophile areimpractical. Thus when the value of K_(p) and/or [Drug]_(free) are low,the maximum preferred lipophile:drug ratio may be limited by practicalconsiderations such as the maximum dose well tolerated by the subject orthe maximum practical size of the dosage form.

Adsorbates

The drug is present in the composition in the form of an adsorbatecomprising a drug and a substrate. At least a major portion of the drugin the adsorbate is amorphous. The term “amorphous” indicates simplythat the drug is not crystalline as indicated by any conventionalmethod, such as by powder X-ray diffraction (PXRD) analysis in which thesharp scattering lines associated with the crystal forms of the drug areabsent or reduced in magnitude or the absence of an endothermictransition at the melting point of the crystalline drug when subjectedto thermal analysis. The term “a major portion” of the drug means thatat least 60% of the drug is in amorphous form, rather than a crystallineform. Preferably, the drug in the adsorbate is substantially amorphous.As used herein, “substantially amorphous” means that the amount of thedrug in amorphous form is at least 80%. More preferably, the drug in theadsorbate is “almost completely amorphous” meaning that the amount ofdrug in the amorphous form is at least 90% as measured by powder X-raydiffraction or differential scanning calorimetry (“DSC”), or any otherstandard quantitative measurement. Most preferably, the drug in theadsorbate is in a completely amorphous form within the detection limitsof the techniques used for characterization.

The adsorbate also includes a high surface area substrate. The substratemay be any material that is inert, meaning that the substrate does notadversely interact with the drug to an unacceptably high degree andwhich is pharmaceutically acceptable. The substrate also has a highsurface area, meaning that the substrate has a surface area of at least20 m²/g, preferably at least 50 m²/g, more preferably at least 100 m²/g,and most preferably at least 180 m²/g. The surface area of the substratemay be measured using standard procedures. One exemplary method is bylow-temperature nitrogen adsorption, based on the Brunauer, Emmett, andTeller (BET) method, well known in the art. As discussed below, thehigher the surface area of the substrate, the higher thedrug-to-substrate ratio that can be achieved and still maintain highconcentration-enhancements and improved physical stability. Thus,effective substrates can have surface areas of up to 200 m²/g, up to 400m²/g and up to 600 m²/g or more. The substrate should also be in theform of small particles ranging in size of from about 5 nm to about 1μm, preferably ranging in size from about 5 nm to about 100 nm. Theseparticles may in turn form agglomerates ranging in size from 10 nm to100 μm. The substrate is also insoluble in the process environment usedto form the adsorbate. That is, where the adsorbate is formed by solventprocessing, the substrate does not dissolve in the solvent. Where theadsorbate is formed by a melt or thermal process, the substrate has asufficiently high melting point that it does not melt.

Exemplary materials which are suitable for the substrate includeinorganic oxides, such as SiO₂, TiO₂, ZnO₂, ZnO, Al₂O₃, MgAlSilicate,CaSilicate, AIOH₂, zeolites, and other inorganic molecular sieves; waterinsoluble polymers, such as cross-linked cellulose acetate phthalate,cross-linked hydroxypropyl methyl cellulose acetate succinate,cross-linked polyvinyl pyrrolidinone, (also known as cross povidone)microcrystalline cellulose, polyethylene/polyvinyl alcohol copolymer,polyethylene polyvinyl pyrrolidone copolymer, cross-linked carboxymethylcellulose, sodium starch glycolate, cross-linked polystyrene divinylbenzene; and activated carbons, including those made by carbonization ofpolymers such as polyimides, polyacrylonitrile, phenolic resins,cellulose acetate, regenerated cellulose, and rayon.

The surface of the substrate may be modified with various substituentsto achieve particular interactions of the drug with the substrate. Forexample, the substrate may have a hydrophobic or hydrophilic surface. Byvarying the terminating groups of substituents attached to thesubstrate, the interaction between the drug and substrate may beinfluenced. For example, where the drug is hydrophobic, it may bedesired to select a substrate having hydrophobic substituents to improvethe binding of the drug to the substrate.

Generally, the interaction of drug with the substrate should besufficiently high such that mobility of the drug in the drug/substrateadsorbate is sufficiently decreased such that the composition hasimproved stability, as described below. However, the drug/substrateinteraction should be sufficiently low such that the drug can readilydesorb from the adsorbate when it is introduced to a use environment,resulting in a high concentration of drug in solution.

The adsorbates are formed so as to form a thin layer of amorphous drugon the surface of the substrate. By “thin layer” is meant a layer thatranges in average thickness from less than one drug molecule to as manyas 10 molecules. When the drug/substrate interaction is large and theaverage drug layer thickness, based on the ratio of the mass ofdrug-to-substrate surface area, is about the dimensions of one molecule,the drug layer is generally termed a “monolayer.”

The adsorption of drug to the substrate may be characterized by a shiftin the infra red (IR) spectra of the drug, indicating interaction of thedrug with the substrate. Such interactions are generally due to Londondispersion forces, dipole-dipole interactions, hydrogen bonding,electron donor-electron acceptor interactions or ionic interactions. Forexample, when the drug torcetrapib is adsorption as a monolayer to asilicone dioxide substrate (Cab-O-Sil M-5P), the C═O peak at about 1700cm⁻is shifted by 20 cm⁻to a lower wavenumber. At higher drug loadings(that is, more than a monolayer of drug), a second peak is observed atthe original C═O position for amorphous drug (that is, amorphous drugnot adsorbed to a substrate). Fitting the FTIR spectra with two gaussianabsorption peaks allows quantification of the relative proportion ofdrug adsorbed as a monolayer and that absorbed in multiple layers.

Additionally, if the adsorbate contains more than 2 or 3 layers of drugmolecules, the physical stability of the adsorbate may be compromised,since the mobility of the drug molecules furthest from the substrate isrelatively high. Thus, crystallization of the drug molecules on a thickadsorbed layer may occur more rapidly than that observed for a thinadsorbed layer.

One exemplary method for forming adsorbates of the present invention is“solvent processing.” Solvent processing consists of dissolution of thedrug in a solvent containing the substrate followed by rapid removal ofthe solvent. The term “solvent” is used broadly and includes mixtures ofsolvents. In general, the substrate will not significantly dissolve inthe solvent and remains solid throughout the process.

First, the substrate is added to a solvent that is capable of dissolvingthe drug. Since it is generally desirable to form adsorbate particlesthat are small, preferably less than about 1 to 10 μm, the solution isagitated to form a suspension of small particles of substrate suspendedin the solvent. Agitation of the solution may be performed by any methodthat is capable of imparting sufficient energy to the solution to breakup agglomerations of substrate particles. A preferred method issonication. Other methods that may be used to break up the particles toform a suspension of substrate in the solvent include high speed mixing,and high shear mechanical mixing. The solution is agitated for asufficient length of time so that the substrate remains suspended in thesolution for at least a few minutes. Often, to ease processing, it isdesirable that the substrate remain suspended for at least 60 minuteswithout agglomeration. However, this is not required for practice of theinvention. The solvent/substrate suspension may be continuously agitatedduring processing to ensure the substrate remains suspended in thesolvent.

The drug is added to the solvent and dissolved. The amount of drug andsubstrate present in the solution is chosen to yield an adsorbate havingthe desired ratio of drug to substrate. In general, good results may beobtained where the solution comprises from 0.1 to 2 wt % drug and from0.1 to 5 wt % substrate. In general, it is desired to maintain theamount of solids in the solution at less than about 10 wt %, as thesubstrate when present at higher concentrations may clog or stick to thesurfaces of the apparatus used to form the adsorbate. The weight ratioof drug to substrate is chosen such that the desired drug-layerthickness is obtained. Generally, better dissolution performance isobtained at lower drug-to-substrate ratios. However, higherdrug-to-substrate weight ratios provide good performance when thesubstrate surface area is high. Typically, drug-to-substrate weightratios are less than 1.0 and often less than 0.25 to obtain preferreddissolution performance.

After the substrate has been agitated and the drug has been dissolved,the solvent is rapidly removed by evaporation or by mixing with anon-solvent. Exemplary processes are spray-drying, spray-coating(pan-coating, fluidized bed coating, etc.), and precipitation by rapidmixing of the solution with CO₂, hexane, heptane, water of appropriatepH, or some other non-solvent. Preferably, removal of the solventresults in a solid adsorbate. To achieve this end, it is generallydesirable to rapidly remove the solvent from the solution such as in aprocess where the solution is atomized and the drug rapidly solidifieson the substrate.

The adsorbates formed by such processes that rapidly “quench” thematerial, that is, bring the material from the dissolved state to thesolid state very rapidly are generally preferred as they result in amaterial with superior physical structure and performance.

In one embodiment, the solvent is removed through the process ofspray-drying. The term spray-drying is used conventionally and broadlyrefers to processes involving breaking up liquid mixtures into smalldroplets (atomization) and rapidly removing solvent from the mixture ina container (spray-drying apparatus) where there is a strong drivingforce for evaporation of solvent from the droplets. The strong drivingforce for solvent evaporation is generally provided by maintaining thepartial pressure of solvent in the spray-drying apparatus well below thevapor pressure of the solvent at the temperature of the drying droplets.This is accomplished by either (1) maintaining the pressure in thespray-drying apparatus at a partial vacuum (e.g., 0.01 to 0.50 atm); (2)mixing the liquid droplets with a warm drying gas; or (3) both. Inaddition, at least a portion of the heat required for evaporation ofsolvent may be provided by heating the spray solution.

Solvents suitable for spray-drying can be water or any organic compoundin which the drug is soluble and the substrate insoluble. Preferably,the solvent is also volatile with a boiling point of about 150° C. orless. In addition, the solvent should have relatively low toxicity andbe removed from the adsorbate to a level that is acceptable according toThe International Committee on Harmonization (ICH) guidelines. Removalof solvent to this level may require a processing step such astray-drying subsequent to the spray-drying or spray-coating process.Preferred solvents include alcohols such as methanol, ethanol,n-propanol, isopropanol, and butanol; ketones such as acetone, methylethyl ketone and methyl iso-butyl ketone; esters such as ethyl acetateand propylacetate; and various other solvents such as acetonitrile,methylene chloride, toluene, and 1,1,1-trichloroethane. Mixtures,particularly mixtures of an organic solvent such as methanol, ethanol oracetone and water are often desirable. Lower volatility solvents such asdimethyl acetamide or dimethylsulfoxide can also be used. Mixtures ofsolvents, such as 50% methanol and 50% acetone, can also be used, as canmixtures with water as long as the drug is sufficiently soluble to makethe spray-drying process practicable.

Generally, the temperature and flow rate of the drying gas is chosen sothat the droplets containing the adsorbate are dry enough by the timethey reach the wall of the apparatus that they are essentially solid,and so that they form a fine powder and do not stick to the apparatuswall. The actual length of time to achieve this level of dryness dependson the size of the droplets. Droplet sizes generally range from 1 μm to500 μm in diameter, with 5 to 150 μm being more typical. The largesurface-to-volume ratio of the droplets and the large driving force forevaporation of solvent leads to actual drying times of a few seconds orless, and more typically less than 0.1 second. Solidification timesshould be less than 100 seconds, preferably less than a few seconds, andmore preferably less than 1 second. In general, to achieve this rapidsolidification of the solution, it is preferred that the size ofdroplets formed during the spray-drying process be less than about 150μm in diameter. The resultant solid particles thus formed are generallyless than about 150 μm in diameter.

Following solidification, the solid powder typically stays in thespray-drying chamber for about 5 to 60 seconds, further evaporatingsolvent from the solid powder. The final solvent content of the solidadsorbate as it exits the dryer should be low, since this reduces themobility of drug molecules in the adsorbate, thereby improving itsstability. Generally, the solvent content of the adsorbate as it leavesthe spray-drying chamber should be less than 10 wt % and preferably lessthan 2 wt %. Following spray-drying, the adsorbate may be dried in asolvent drier, such as a tray-dryer or a fluidized-bed dryer to removeresidual solvents.

Spray-drying processes and spray-drying equipment are describedgenerally in Perry's Chemical Engineers' Handbook, Sixth Edition (R. H.Perry, D. W. Green, J. O. Maloney, eds.) McGraw-Hill Book Co. 1984,pages 20-54 to 20-57. More details on spray-drying processes andequipment are reviewed by Marshall “Atomization and Spray-Drying,” 50Chem. Eng. Prog. Monogr. Series 2 (1954).

As mentioned above, preferred adsorbates of the present invention aremade by processes such as spray-drying that rapidly bring the drug fromthe dissolved state to the solid adsorbed state. Such adsorbates have aunique physical structure and have greater physical stability anddissolution performance relative to those made by processes that slowlyremove solvent.

Another method to produce adsorbates comprising amorphous drug adsorbedto a substrate is a thermal process. Here, the drug is melted and thencoated onto the surface of substrates using, for example, a twin-screwextruder. In one exemplary technique the drug is first uniformly blendedwith the substrate. The blend may be prepared using methods well knownin the art for obtaining powdered mixtures with high content uniformity.For example, the drug and substrate may first be independently milled toobtain a small particle size (e.g., less than about 100 μm) and thenadded to a V blender and blended for 20 minutes. This blend may then bemilled to break up any agglomerates, and then blended in a V blender foran additional period of time to obtain a uniform preblend of drug andsubstrate.

This preblend of drug and substrate is fed into an extruder. By“extruder” is meant a device or collection of devices that creates amolten extrudate by heat and/or shear forces and/or produces a uniformlymixed extrudate. Such devices include, but are not limited tosingle-screw extruders; twin-screw extruders, including co-rotating,counter-rotating, intermeshing, and non-intermeshing extruders; multiplescrew extruders; ram extruders, consisting of a heated cylinder and apiston for extruding the molten extrudate; gear-pump extruders,consisting of a heated gear pump, generally counter-rotating, thatsimultaneously heats and pumps the molten feed; and conveyer extruders.Conveyer extruders comprise a conveyer means for transporting solidand/or powdered feeds, such, such as a screw conveyer or pneumaticconveyer, and a pump. At least a portion of the conveyer means is heatedto a sufficiently high temperature to produce the extrudate. Optionally,an in-line mixer may be used before or after the pump to ensure theextrudate is substantially homogeneous. In each of these extruders thecomposition is mixed to form a uniformly mixed extrudate. Such mixingmay be accomplished by various mechanical and processing means,including mixing elements, kneading elements, and shear mixing bybackflow.

In the case of a twin-screw extruder, the screw configuration and mixingpaddles are set so as to provide a high degree of fill of the screwsections for efficient heat transfer from the barrel and avoidance ofexcessive flow restriction. The screw configuration is also selectedsuch that there is sufficient mechanical energy (i.e., shear) to breakapart any aggregated substrate still remaining after the preblend stepand to uniformly mix the drug and substrates. The barrel temperatureshould be ramped from approximately room temperature at the feed area toslightly above the melting temperature of the drug in the last barrelzone (discharge end). This technique is applicable for any drug with amelting temperature low enough to melt in the extruder (<400° C.), andfor drugs with acceptable chemical stability at the elevatedtemperatures. Thermal processes such as melt-extrusion processes andequipment are described generally in Encyclopedia of ChemicalTechnology, 4th Edition (John Wiley & Sons, 1991).

A processing aid may optionally be blended with such drug/substratemixtures to form a three-component (or more) preblend that is fed to theextruder. One object of such additives is to lower the temperaturerequired for liquefaction of the drug. Thus, the additive typically hasa melt point below that of the drug and the drug is typically soluble inthe molten additive. The additive may be a volatile material such aswater that evaporates from the composition or it may have a high boilingpoint, such as a mono- or di-glyceride such that it remains part of thecomposition following processing.

Analogous to the solvent processing method described above, it ispreferred to rapidly “quench” the molten material as it exits (isdischarged from) the extruder. Any method that results in rapidsolidification of the drug as a solid adsorbed layer on the substrate issuitable. Exemplary methods are contact with a cooling fluid such as acold gas or liquid. Alternatively, the material may enter a cooled millwhere heat is transferred from the material at the same time as it ismilled into a fine powder with granule sizes from about 100 nm to 100μm.

Alternatively, a solvent, such as water, can be added to the preblendfed to a twin screw extruder. The screw configuration is designed sothat there is sufficient pressure in the extruder to preventvaporization of the solvent at the temperatures required to melt thedrug. When the extrudate exits the extruder, the sudden decrease inpressure causes rapid vaporization of the solvent, leading to rapidcooling and congealing of the adsorbate material. Any residual solventin the composition can be removed using conventional drying technologysuch as a tray drier or a fluidized-bed drier.

Thus, preferred adsorbates of the present invention may be made by anysolvent or thermal process that rapidly solidifies (that is, quenches)the material by solvent removal, precipitation with a nonsolvent orcooling. Such materials, termed “rapidly quenched adsorbates,” havesuperior properties to adsorbates made by other methods.

In particular, when such “rapidly quenched adsorbates” are delivered toan aqueous use environment, they provide enhanced drug concentrations.Specifically, such rapidly quenched adsorbates provide a higher maximumfree drug concentration or a higher maximum total dissolved drugconcentration than that provided by a control, termed a“slow-evaporation control composition,” formed by evaporating thesolvent from a suspension of the same substrate in a solution of drugover a period of 30 minutes or more.

In addition, such rapidly quenched adsorbates may also show improvedphysical stability, slower crystallization rates and superior thermalproperties relative to the slow-evaporation control composition.

The drug/substrate adsorbates resulting from the various preparationtechniques are solid materials comprising about 5 wt % to 90 wt % drug.The materials are typically agglomerates of particles, the agglomerateshaving a mean diameter ranging from 10 nm to 100 μm. The agglomeratestypically retain the fine particulate nature of the starting substrate.In the case of high surface area silicon dioxide, these consist ofbranched chains composed of many particles with mean diameters of about10 to 30 nm, or agglomerates of very small spheres (<10 μm).

For adsorbates in which the substrate has a surface area ofapproximately 200 m²/g, it is believed that for low drug loadings (underabout 12 wt %), the drug is present primarily as drug molecules directlyadsorbed onto the substrate surface. For such high surface areasubstrates, there is sufficient surface area for all drug to be directlyadsorbed to the substrate up to a drug-to-substrate weight ratio ofabout 8. Drug adsorbed onto such substrates can be considered a monolayer. Drug adsorbed in this way is noncrystalline and thus may beconsidered amorphous. However, the interaction of the drug and substratesurface give the drug substantially different physical properties thanbulk amorphous drug alone. At greater drug loadings in the adsorbate, itis believed that the drug forms additional layers of amorphous drug ontop of the initial monolayer. While not wishing to be bound by anyparticular theory, it is believed that the interaction of the thinlayer(s) of the drug with the substrate improves the physical stabilityof the drug by decreasing the mobility of the drug on the substraterelative to the mobility of drug in a bulk amorphous material. This mayresult in improved physical stability by hindering diffusion of drug,and thus inhibiting crystal formation.

As the surface area of the substrate increases, the amount of drug thatcan be incorporated into the adsorbate while maintaining a monolayer (orless) of drug also increases. For example, if the substrate has asurface area of 400 m²/g, the drug loading that leads to a monolayer isapproximately 21 wt %, while if the substrate has a surface area of 600m²/g, the drug loading can be about 29% while maintaining a monolayer ofdrug on the substrate. Thus, it is desirable to use a substrate with ashigh a surface area as possible to obtain high drug loadings. Suchvalues for the relationship of “drug loading” to substrate surface areaare only approximate and depend on the specific size, shape, andorientation of each specific drug.

The amorphous drug adsorbed to the substrate is in a relatively highenergy state when dosed to an aqueous use environment. While not wishingto be bound by any particular theory or mechanism of action, it isbelieved this high energy state is due to generally reduced drug-druginteractions of the drug adsorbed to the substrate compared withamorphous or crystalline drug alone. The substrate stabilizes thishigh-energy amorphous form of the drug. Thus, when introduced to anaqueous use environment, the drug/substrate adsorbate may provideenhanced aqueous concentration of drug.

The physical nature of this stabilized high-energy state of theamorphous drug may be characterized using IR spectroscopy. Generally,interactions of the drug with the substrate are characterized by a shiftin the IR spectrum to a lower wave number, indicating hydrogen bondingof the drug to the substrate. In addition, the physical nature of theadsorbed drug may be evaluated by techniques such as vapor absorption,thermal calorimetry such as differential scanning calorimetry (DSC), orpowder x-ray diffraction.

The adsorbate may also include optional additional components, inaddition to the processing aids described above, such as surfactants, pHmodifiers, disintegrants, binders, lubricants, etc. These materials mayhelp improve processing, performance, or help in preparing dosage formscontaining the adsorbates, as discussed below.

One particularly preferred optional additional component is aconcentration-enhancing polymer. While the drug/substrate adsorbateprovides enhanced concentration of drug in a use environment relative toamorphous drug alone, the inclusion of a concentration-enhancing polymerin the adsorbate may improve the observed enhancement and/or allow forsustaining the enhanced concentration for a longer period of time.

The compositions of the present invention containingconcentration-enhancing polymers may be prepared through a variety ofmethods. The concentration-enhancing polymer may be co-adsorbed onto thesubstrate with the drug, so as to form an amorphous dispersion of drugand polymer adsorbed onto the substrate. Alternatively, theconcentration-enhancing polymer may be combined with the drug/substrateadsorbate in a mixture.

In one preferred method for combining the adsorbate andconcentration-enhancing polymer, the concentration-enhancing polymer isco-adsorbed with the drug onto the substrate. This results in anamorphous dispersion of drug and polymer adsorbed onto the surface ofthe substrate. The concentration-enhancing polymer may be co-adsorbedwith the drug on the substrate using any method that results in a thinlayer of amorphous drug and polymer adsorbed onto the surface of thesubstrate. The layer may range in thickness from a complete ordiscontinuous layer of drug and polymer molecules adsorbed directly tothe substrate surface, up to a layer of drug and polymer up to athickness of about the size of 5 to 10 polymer or drug molecules. Atleast a major portion of the drug present in the adsorbate is amorphous.Preferably, the drug in the adsorbate is substantially amorphous, andmore preferably, the drug is almost completely amorphous. While thedispersion of drug and polymer adsorbed onto the substrate may havedrug-rich domains and polymer-rich domains, in one embodiment thedispersion is substantially homogeneous, meaning that the amount of thedrug present in drug-rich amorphous domains within the dispersion isless than 20%. Often, for such materials the dispersion is “completelyhomogeneous,” meaning that the amount of drug in drug-rich domains isless than 10%.

One method for adsorbing the concentration-enhancing polymer onto thesubstrate with the drug is to form the adsorbate using a solvent processas described above. In that case, the concentration-enhancing polymerand drug are dissolved in a common solvent to which the substrate hadbeen added. By “common solvent” is meant a solvent capable of dissolvingboth the drug and the concentration-enhancing polymer.

In one exemplary method, the substrate is first added to the commonsolvent and sonicated. The concentration-enhancing polymer is then addedto the solution and dissolved. The drug is then added to the solvent anddissolved. The solvent is then rapidly removed from the resultingsolution of dissolved drug, dissolved polymer and suspended substrate.The resulting particles of adsorbate are then collected and dried.

An alternative method to co-adsorb drug and polymer onto a substrate isusing a thermal process as described above. In one exemplary method,drug, concentration-enhancing polymer, and substrate are preblended andfed to an extruder. The extruder is designed to melt the drug andpolymer, resulting in adsorption onto the substrate. The composition isthen rapidly cooled to form a rapidly quenched adsorbate, as describedabove. Additives, such as water, solvents, low-melting-point solids, orplasticizers may be added to the preblend to reduce the melting point ofthe polymer and allow for lower processing temperatures.

The resulting drug/polymer/substrate adsorbates may comprise from 2 wt %to 90 wt % drug, from 2 to 90 wt % substrate, and from 5 wt % to 95 wt %concentration-enhancing polymer. The mean diameter of thedrug/polymer/substrate adsorbates ranges from about 5 nm to about 100μm, and the adsorbates are typically agglomerates of particles havingmean diameters of about 5 nm to 50 nm.

Concentration-Enhancing Polymers

Concentration-enhancing polymers suitable for use in the various aspectsof the present invention should be pharmaceutically acceptable, andshould have at least some solubility in aqueous solution atphysiologically relevant pHs (e.g. 1-8). Almost any neutral or ionizablepolymer that has an aqueous-solubility of at least 0.1 mg/mL over atleast a portion of the pH range of 1-8 may be suitable.

It is preferred that the concentration-enhancing polymers be“amphiphilic” in nature, meaning that the polymer has hydrophobic andhydrophilic portions. Amphiphilic polymers are preferred because it isbelieved that such polymers tend to have relatively strong interactionswith the drug and may promote the formation of various types ofpolymer/drug assemblies in solution. A particularly preferred class ofamphiphilic polymers are those that are ionizable, the ionizableportions of such polymers, when ionized, constituting at least a portionof the hydrophilic portions of the polymer. For example, while notwishing to be bound by a particular theory, such polymer/drug assembliesmay comprise hydrophobic drug clusters surrounded by theconcentration-enhancing polymer with the polymer's hydrophobic regionsturned inward towards the drug and the hydrophilic regions of thepolymer turned outward toward the aqueous environment. Alternatively,depending on the specific chemical nature of the drug, the ionizedfunctional groups of the polymer may associate, for example, via ionpairing or hydrogen bonds, with ionic or polar groups of the drug. Inthe case of ionizable polymers, the hydrophilic regions of the polymerwould include the ionized functional groups. In addition, the repulsionof the like charges of the ionized groups of such polymers (where thepolymer is ionizable) may serve to limit the size of the polymer/drugassemblies to the nanometer or submicron scale. Suchdrug/concentration-enhancing polymer assemblies in solution may wellresemble charged polymeric micellar-like structures. In any case,regardless of the mechanism of action, the inventors have observed thatsuch amphiphilic polymers, particularly ionizable cellulosic polymerssuch as those listed below, have been shown to interact with drug so asto maintain a higher concentration of drug in an aqueous useenvironment.

One class of polymers suitable for use with the present inventioncomprises neutral non-cellulosic polymers. Exemplary polymers include:vinyl polymers and copolymers having at least one substituent selectedfrom the group comprising hydroxyl, alkylacyloxy, and cyclicamido; vinylcopolymers of at least one hydrophilic, hydroxyl-containing repeat unitand at least one hydrophobic, alkyl- or aryl-containing repeat unit;polyvinyl alcohols that have at least a portion of their repeat units inthe unhydrolyzed (vinyl acetate) form; polyvinyl alcohol polyvinylacetate copolymers; polyvinyl pyrrolidone; polyethylene polyvinylalcohol copolymers, and polyoxyethylene-polyoxypropylene blockcopolymers (also referred to as poloxamers).

Another class of polymers suitable for use with the present inventioncomprises ionizable non-cellulosic polymers. Exemplary polymers include:carboxylic acid-functionalized vinyl polymers, such as the carboxylicacid functionalized polymethacrylates and carboxylic acid functionalizedpolyacrylates such as the EUDRAGITS® manufactured by Rohm Tech Inc., ofMalden, Mass.; amine-functionalized polyacrylates and polymethacrylates;high molecular weight proteins such as gelatin and albumin; andcarboxylic acid functionalized starches such as starch glycolate.

Non-cellulosic polymers that are amphiphilic are copolymers of arelatively hydrophilic and a relatively hydrophobic monomer. Examplesinclude acrylate and methacrylate copolymers. Exemplary commercialgrades of such copolymers include the EUDRAGITS, which are copolymers ofmethacrylates and acrylates.

A preferred class of polymers comprises ionizable and neutral (ornon-ionizable) cellulosic polymers with at least one ester- and/orether-linked substituent in which the polymer has a degree ofsubstitution of at least 0.05 for each substituent. It should be notedthat in the polymer nomenclature used herein, ether-linked substituentsare recited prior to “cellulose” as the moiety attached to the ethergroup; for example, “ethylbenzoic acid cellulose” has ethoxybenzoic acidsubstituents. Analogously, ester-linked substituents are recited after“cellulose” as the carboxylate; for example, “cellulose phthalate” hasone carboxylic acid of each phthalate moiety ester-linked to the polymerand the other carboxylic acid unreacted.

It should also be noted that a polymer name such as “cellulose acetatephthalate” (CAP) refers to any of the family of cellulosic polymers thathave acetate and phthalate substituents attached via ester linkages to asignificant fraction of the cellulosic polymer's hydroxyl groups.Generally, the degree of substitution of each substituent can range from0.05 to 2.9 as long as the other criteria of the polymer are met.“Degree of substitution” refers to the average number of the threehydroxyls per saccharide repeat unit on the cellulose chain that havebeen substituted. For example, if all of the hydroxyls on the cellulosechain have been phthalate substituted, the phthalate degree ofsubstitution is 3. Also included within each polymer family type arecellulosic polymers that have additional substituents added inrelatively small amounts that do not substantially alter the performanceof the polymer.

Amphiphilic cellulosics comprise polymers in which the parent cellulosepolymer has been substituted at any or all of the 3 hydroxyl groupspresent on each saccharide repeat unit with at least one relativelyhydrophobic substituent. Hydrophobic substituents may be essentially anysubstituent that, if substituted to a high enough level or degree ofsubstitution, can render the cellulosic polymer essentially aqueousinsoluble. Examples of hydrophobic substituents include ether-linkedalkyl groups such as methyl, ethyl, propyl, butyl, etc.; or ester-linkedalkyl groups such as acetate, propionate, butyrate, etc.; and ether-and/or ester-linked aryl groups such as phenyl, benzoate, or phenylate.Hydrophilic regions of the polymer can be either those portions that arerelatively unsubstituted, since the unsubstituted hydroxyls arethemselves relatively hydrophilic, or those regions that are substitutedwith hydrophilic substituents. Hydrophilic substituents include ether-or ester-linked nonionizable groups such as the hydroxy alkylsubstituents hydroxyethyl, hydroxypropyl, and the alkyl ether groupssuch as ethoxyethoxy or methoxyethoxy. Particularly preferredhydrophilic substituents are those that are ether- or ester-linkedionizable groups such as carboxylic acids, thiocarboxylic acids,substituted phenoxy groups, amines, phosphates or sulfonates.

One class of cellulosic polymers comprises neutral polymers, meaningthat the polymers are substantially non-ionizable in aqueous solution.Such polymers contain non-ionizable substituents, which may be eitherether-linked or ester-linked. Exemplary ether-linked non-ionizablesubstituents include: alkyl groups, such as methyl, ethyl, propyl,butyl, etc.; hydroxy alkyl groups such as hydroxymethyl, hydroxyethyl,hydroxypropyl, etc.; and aryl groups such as phenyl. Exemplaryester-linked non-ionizable substituents include: alkyl groups, such asacetate, propionate, butyrate, etc.; and aryl groups such as phenylate.However, when aryl groups are included, the polymer may need to includea sufficient amount of a hydrophilic substituent so that the polymer hasat least some water solubility at any physiologically relevant pH offrom 1 to 8.

Exemplary non-ionizable cellulosic polymers that may be used as thepolymer include: hydroxypropyl methyl cellulose acetate, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methyl cellulose,hydroxyethyl methyl cellulose, hydroxyethyl cellulose acetate, andhydroxyethyl ethyl cellulose.

A preferred set of non-ionizable (neutral) cellulosic polymers are thosethat are amphiphilic. Exemplary polymers include hydroxypropyl methylcellulose and hydroxypropyl cellulose acetate, where cellulosic repeatunits that have relatively high numbers of methyl or acetatesubstituents relative to the unsubstituted hydroxyl or hydroxypropylsubstituents constitute hydrophobic regions relative to other repeatunits on the polymer.

A preferred class of cellulosic polymers comprises polymers that are atleast partially ionizable at physiologically relevant pH and include atleast one ionizable substituent, which may be either ether-linked orester-linked. Exemplary ether-linked ionizable substituents include:carboxylic acids, such as acetic acid, propionic acid, benzoic acid,salicylic acid, alkoxybenzoic acids such as ethoxybenzoic acid orpropoxybenzoic acid, the various isomers of alkoxyphthalic acid such asethoxyphthalic acid and ethoxyisophthalic acid, the various isomers ofalkoxynicotinic acid such as ethoxynicotinic acid, and the variousisomers of picolinic acid such as ethoxypicolinic acid, etc.;thiocarboxylic acids, such as thioacetic acid; substituted phenoxygroups, such as hydroxyphenoxy, etc.; amines, such as aminoethoxy,diethylaminoethoxy, trimethylaminoethoxy, etc.; phosphates, such asphosphate ethoxy; and sulfonates, such as sulphonate ethoxy. Exemplaryester linked ionizable substituents include: carboxylic acids, such assuccinate, citrate, phthalate, terephthalate, isophthalate,trimellitate, and the various isomers of pyridinedicarboxylic acid,etc.; thiocarboxylic acids, such as thiosuccinate; substituted phenoxygroups, such as amino salicylic acid; amines, such as natural orsynthetic amino acids, such as alanine or phenylalanine; phosphates,such as acetyl phosphate; and sulfonates, such as acetyl sulfonate. Foraromatic-substituted polymers to also have the requisite aqueoussolubility, it is also desirable that sufficient hydrophilic groups suchas hydroxypropyl or carboxylic acid functional groups be attached to thepolymer to render the polymer aqueous soluble at least at pH valueswhere any ionizable groups are ionized. In some cases, the aromaticsubstituent may itself be ionizable, such as phthalate or trimellitatesubstituents.

Exemplary cellulosic polymers that are at least partially ionized atphysiologically relevant pHs include: hydroxypropyl methyl celluloseacetate succinate (HPMCAS), hydroxypropyl methyl cellulose succinate,hydroxypropyl cellulose acetate succinate, hydroxyethyl methyl cellulosesuccinate, hydroxyethyl cellulose acetate succinate, hydroxypropylmethyl cellulose phthalate (HPMCP), hydroxyethyl methyl celluloseacetate succinate, hydroxyethyl methyl cellulose acetate phthalate,carboxyethyl cellulose, ethylcarboxymethyl cellulose (also referred toas carboxymethylethyl cellulose or CMEC), carboxymethyl cellulose,cellulose acetate phthalate (CAP), methyl cellulose acetate phthalate,ethyl cellulose acetate phthalate, hydroxypropyl cellulose acetatephthalate, hydroxypropyl methyl cellulose acetate phthalate,hydroxypropyl cellulose acetate phthalate succinate, hydroxypropylmethyl cellulose acetate succinate phthalate, hydroxypropyl methylcellulose succinate phthalate, cellulose propionate phthalate,hydroxypropyl cellulose butyrate phthalate, cellulose acetatetrimellitate (CAT), methyl cellulose acetate trimellitate, ethylcellulose acetate trimellitate, hydroxypropyl cellulose acetatetrimellitate, hydroxypropyl methyl cellulose acetate trimellitate,hydroxypropyl cellulose acetate trimellitate succinate, cellulosepropionate trimellitate, cellulose butyrate trimellitate, celluloseacetate terephthalate, cellulose acetate isophthalate, cellulose acetatepyridinedicarboxylate, salicylic acid cellulose acetate, hydroxypropylsalicylic acid cellulose acetate, ethylbenzoic acid cellulose acetate,hydroxypropyl ethylbenzoic acid cellulose acetate, ethyl phthalic acidcellulose acetate, ethyl nicotinic acid cellulose acetate, and ethylpicolinic acid cellulose acetate. Of these cellulosic polymers that areat least partially ionized at physiologically relevant pHs, those thatthe inventors have found to be most preferred are HPMCAS, HPMCP, CAP,CAT, carboxyethyl cellulose, carboxymethyl cellulose, and ethylcarboxymethyl cellulose.

Another preferred class of polymers consists of neutralized acidicpolymers. By “neutralized acidic polymer” is meant any acidic polymerfor which a significant fraction of the “acidic moieties” or “acidicsubstituents” have been “neutralized”; that is, exist in theirdeprotonated form. By “acidic polymer” is meant any polymer thatpossesses a significant number of acidic moieties. In general, asignificant number of acidic moieties would be greater than or equal toabout 0.1 milliequivalents of acidic moieties per gram of polymer.“Acidic moieties” include any functional groups that are sufficientlyacidic that, in contact with or dissolved in water, can at leastpartially donate a hydrogen cation to water and thus increase thehydrogen-ion concentration. This definition includes any functionalgroup or “substituent,” as it is termed when the functional group iscovalently attached to a polymer that has a pKa of less than about 10.Exemplary classes of functional groups that are included in the abovedescription include carboxylic acids, thiocarboxylic acids, phosphates,phenolic groups, and sulfonates. Such functional groups may make up theprimary structure of the polymer such as for polyacrylic acid, but moregenerally are covalently attached to the backbone of the parent polymerand thus are termed “substituents.” Neutralized acidic polymers aredescribed in more detail in commonly assigned U.S. patent applicationSer. No. 60/300,256 entitled “Pharmaceutical Compositions of Drugs andNeutralized Acidic Polymers” filed Jun. 22, 2001, the relevantdisclosure of which is incorporated by reference.

While specific polymers have been discussed as being suitable for use inthe mixtures of the present invention, blends of such polymers may alsobe suitable. Thus the term “concentration-enhancing polymer” is intendedto include blends of polymers in addition to a single species ofpolymer.

Preparation of Compositions

Compositions of the present invention may be prepared according to anytechnique that results in a mixture comprising (1) an adsorbatecomprising a low-solubility drug and a high surface area substrate,wherein at least a major portion of the drug is amorphous, and (2) alipophilic microphase-forming material. In one method, an adsorbatecomprising the drug, substrate, optional concentration-enhancingpolymer, and lipophilic microphase-forming material is formed so thatthe lipophilic microphase-forming material is co-adsorbed to thesubstrate along with the drug and optional concentration-enhancingpolymer. Alternatively, the drug/substrate adsorbate with optionalconcentration-enhancing polymer may be formed and then mixed with thelipophilic microphase-forming material so that the lipophilicmicrophase-forming material is mixed with the adsorbate. As yet anotheralternative, the drug/substrate adsorbate with optionalconcentration-enhancing polymer may be prepared and then co-administeredwith a lipophilic microphase-forming material to a use environment, sothat the adsorbate and lipophilic microphase-forming material are bothpresent in the use environment.

In many cases, to aid the dispersing of the lipophilicmicrophase-forming material in the use environment, it is oftendesirable to disperse the lipophilic microphase-forming material in awater soluble or water dispersible matrix prior to forming the mixture.Alternatively, the lipophilic microphase-forming material may beadsorbed to a water insoluble substrate such as the high surface areasubstrates discussed above for formation of the drug adsorbate,including dibasic calcium phosphate, calcium carbonate, microcrystallinecellulose, silicon dioxide calcium silicate; clays, such as kaolin(hydrated aluminum silicate), bentonite (hydrated aluminum silicate),hectorite and Veegum®; silicon dioxide (Cab-O-Sil®) or Aerosil®);magnesium trisilicate; aluminum hydroxide; magnesium hydroxide,magnesium oxide or talc. Highly porous materials such as calciumsilicate are preferred. In one embodiment, the lipophilicmicrophase-forming material is adsorbed to a concentration-enhancingpolymer, such as those previously discussed. When the lipophilicmicrophase-forming material is dispersed in a water dispersible matrix,the dispersion may be formed by any of the processes describedpreviously for forming the drug/substrate adsorbate including thermalprocesses such as extrusion, solvent processes such as spray-drying, aswell as conventional wet and dry granulation processes. Followingforming the adsorbate dispersion or granule of lipophilicmicrophase-forming material the dispersion or granule containing thelipophilic microphase-forming material may then be blended with thedrug/substrate adsorbate.

When it is desired to adsorb (or absorb) the lipophilicmicrophase-forming material onto a solid substrate, the lipophilicmicrophase-forming material may be adsorbed onto the solid substrateusing any conventional method. In one exemplary method, the substrate isinitially dried to remove water. The lipophilic microphase-formingmaterial is then combined with the substrate. The lipophilicmicrophase-forming material may be combined with the substrate by theuse of a planetary mixer, a Z-blade mixer, a rotogranulator or similarequipment. Preferably, the amount of lipophilic microphase-formingmaterial is kept sufficiently low so that the mixture of lipophilicmicrophase-forming material and solid substrate forms a free-flowingpowder. The proportion of lipophilic microphase-forming material tosolid substrate preferably is less than about 4:1 (wt:wt) lipophilicmicrophase-forming material to solid substrate. As the weight ratio oflipophilic microphase-forming material to substrate increases, thematerial becomes cake-like, and then oily or slurry-like. The particularratio will depend on the porosity of the substrate and the nature of thelipophilic microphase-forming material. The lipophilicmicrophase-forming material may be diluted in a solvent such as methanolprior to adsorbing the lipophilic microphase-forming material to thesolid substrate. The resulting slurry is dried, for example in a vacuumdesiccator, to form a solid material comprising the lipophilicmicrophase-forming material and substrate. This solid material may thenbe combined with the drug/substrate adsorbate to form a composition ofthe present invention.

Mixing methods include convective mixing, shear mixing, or diffusivemixing. Convective mixing involves moving a relatively large mass ofmaterial from one part of a powder bed to another, by means of blades orpaddles, revolving screw, or an inversion of the powder bed. Shearmixing occurs when slip planes are formed in the material to be mixed.Diffusive mixing involves an exchange of position by single particles.These mixing processes can be performed using equipment in batch orcontinuous mode. Tumbling mixers (e.g., twin-shell) are commonly usedequipment for batch processing. Continuous mixing can be used to improvecomposition uniformity. Continuous mixers include “in-line” mixers andextruders. Extruders may be single screw or twin-screw. Twin-screwextruders may turn in the same or opposite direction.

Milling may also be employed to combine the adsorbate and the lipophilicmicrophase-forming material. Milling is the mechanical process ofreducing the particle size of solids (comminution). The most commontypes of milling equipment are the rotary cutter, the hammer, theroller, and fluid energy mills. Equipment choice depends on thecharacteristics of the ingredients in the composition (e.g., soft,abrasive, or friable). Wet- or dry-milling techniques can be chosen forseveral of these processes, also depending on the characteristics of theingredients (e.g. adsorbate stability in solvent). The milling processmay serve simultaneously as a mixing process if the feed materials areheterogeneous. Conventional mixing and milling processes suitable foruse in the present invention are discussed more fully in Lachman, etal., The Theory and Practice of Industrial Pharmacy (3d Ed. 1986).

The adsorbate and lipophilic microphase-forming material may also becombined by dry- or wet-granulating processes.

In another embodiment, the adsorbate and lipophilic microphase-formingmaterial may be co-administered to the environment of use. By“co-administered” is meant that the adsorbate and lipophilicmicrophase-forming material are administered separately from each otherto the use environment. In one embodiment, the adsorbate and lipophilicmicrophase-forming material are co-administered within the same generaltime frame as each other, such as within 60 minutes, preferably within30 minutes, more preferably within 15 minutes of each other.

Concentration-Enhancement

The compositions of the present invention provideconcentration-enhancement in a use environment relative to one or morecontrol compositions. The compositions of the present invention mayprovide concentration-enhancement relative to a first controlcomposition consisting essentially of the drug/substrate adsorbate butwithout any lipophilic microphase forming material present. Thus, thelipophilic microphase forming material is either present in thecomposition or co-administered in a sufficient amount to provideconcentration enhancement (as described more fully below) relative to afirst control consisting essentially of an equivalent amount of thedrug/substrate adsorbate but with no lipophilic microphase formingmaterial present. That is, the first control composition is identical tothe composition comprising the drug/substrate adsorbate and thelipophilic microphase-forming material except for the absence of thelipophilic microphase-forming material.

Alternatively, the compositions of the present invention provideconcentration enhancement relative to a second control compositionconsisting essentially of the same lipophilic microphase-formingmaterial combined with crystalline drug in an amount equivalent to theamount of drug in the test composition, but with the drug not adsorbedto the high surface area substrate. Thus, the second control compositionis identical to the composition of the invention except that the drug isin the form of crystalline drug rather than amorphous drug adsorbed to ahigh surface area substrate. In cases where more than one crystal formof the drug is known, the control composition consists of thecrystalline form that is most thermodynamically stable at ambientconditions (25° C. and 50% relative humidity). In cases where nocrystalline form of the drug is known, unadsorbed amorphous drug may besubstituted for crystalline drug.

At a minimum, compositions of the present invention provideconcentration enhancement in a use environment relative to at least oneof the two above controls. Preferably, compositions of the presentinvention will provide concentration enhancement in a use environmentrelative to both of the above two controls.

Compositions comprising a drug/substrate adsorbate and lipophilicmicrophase-forming material provide concentration-enhancement in eitheran in vivo or in vitro use environment. In an in vivo use environment,the concentration-enhancement may result in either enhanced relativebioavailability and/or a more regular fed/fasted bioavailability ratio(that is, a fed/fasted bioavailability ratio closer to 1). In an invitro use environment, concentration enhancement may be either enhanceddrug concentration in highly mobile drug species, reduced precipitate,enhanced maximum drug concentration, or enhanced dissolution area underthe concentration Versus time curve (AUC).

As used herein, a “use environment” can be either the in vivoenvironment of the GI tract of an animal, such as a mammal andparticularly a human, or the in vitro environment of a test solution,such as phosphate buffered saline (PBS). Concentration enhancement maybe determined through either in vivo tests or through in vitrodissolution tests. A composition of the present invention meets theconcentration enhancement criteria in at least one of the above testenvironments.

In one aspect, the compositions comprising an adsorbate and lipophilicmicrophase-forming material provide improved relative bioavailabilityrelative to either the first control composition, the second controlcomposition, or preferably both. Relative bioavailability may be testedin vivo in animals or humans using conventional methods for making sucha determination. An in vivo test, such as a crossover study, may be usedto determine whether a test composition provides an enhanced relativebioavailability compared with one or both control compositions. It is tobe understood by those skilled in the art that such in vivo tests shouldbe carried out under fasted conditions. In an in vivo crossover study a“test composition” of adsorbate and lipophilic microphase-formingmaterial is dosed to half a group of test subjects and, after anappropriate washout period (e.g., one week) the same subjects are dosedwith a control composition. As described above, the control compositionmay be either the first control composition, which consists of theadsorbate with no lipophilic microphase-forming material present, or thesecond control composition, which consists of an equivalent amount ofthe drug in crystalline form and an equivalent amount of the lipophilicmicrophase-forming material. The other half of the group is dosed withthe control composition first, followed by the test composition. Therelative bioavailability is measured as the concentration in the blood(serum or plasma) versus time area under the curve (AUC) determined forthe test group divided by the AUC in the blood provided by the controlcomposition. Preferably, this test/control ratio is determined for eachsubject, and then the ratios are averaged over all subjects in thestudy. In vivo determinations of AUC can be made by plotting the serumor plasma concentration of drug along the ordinate (y-axis) against timealong the abscissa x-axis).

To demonstrate improved bioavailability relative to the first controlcomposition and the second control composition, a “three-way in vivocrossover” study may be conducted where the three compositions are thetest composition, the first control composition and the secondcomposition.

A preferred embodiment is one in which the relative bioavailability ofthe test composition is at least 1.25 relative to either the firstcontrol composition or the second control composition when tested underfasted conditions. (That is, the AUC in the blood provided by the testcomposition is at least 1.25-fold the AUC provided by the controlcomposition.) The relative bioavailability may be at least 2.0, and morepreferably at least 3.0, relative to either control composition. Thedetermination of AUCs is a well-known procedure and is described, forexample, in Welling, “Pharmacokinetics Processes and Mathematics,” ACSMonograph 185 (1986). An even more preferred embodiment of the presentinvention is one for which the relative bioavailability of the testcomposition is at least 1.25-fold relative to both the first controlcomposition and the second control composition.

Alternatively, in another separate aspect, the compositions comprisingan adsorbate and lipophilic microphase-forming material provide moreregular absorption. In this aspect, the compositions provide afed/fasted bioavailability ratio that is near 1.0. By “fed/fastedbioavailability ratio” is meant the AUC in the blood provided by acomposition dosed to a subject in the fed state, divided by the AUC inthe blood provided by the same composition dosed to a subject in thefasted state. By “subject in the fed state” is meant a subject who haseaten a Food and Drug Administration (FDA)-recommended standard high fatbreakfast within a period of twenty minutes, and then ingested (i.e.,swallowed) the test dosage form essentially immediately thereafter. Astandard high-fat breakfast consists of, for example, two eggs fried inone tablespoon of butter, two strips of bacon, six ounces of hash brownpotatoes, two pieces of toast with two teaspoons of butter and two patsof jelly, and eight ounces of whole milk. This standard high-fatbreakfast contains approximately 964 calories, 54% supplied as fat (58gm) and 12% supplied as protein, calculated using the monograph“Nutritive Value of Foods”, U.S. Department of Agriculture Home andGarden Bulletin Number 72. Additional food can also be consumed withinthe twenty-minute period and the subject still qualifies as “fed”. A“subject in the fasted state” for purposes of definition is one who hasnot eaten for at least eight hours, typically overnight, prior toingestion of the dosage form.

Thus, a preferred composition of the present invention comprising anadsorbate and a lipophilic microphase forming material provides afed/fasted bioavailability ratio of from about 0.5 to about 2.0.Preferably, the compositions provide a fed/fasted bioavailability ratioof from about 0.67 to about 1.5, and more preferably of from about 0.8to about 1.25. Preferably, the composition of the present inventionprovides a fed/fasted bioavailability ratio that is closer to 1 than atleast one of the first control compositions and the second composition,more preferably both compositions.

Alternatively, the concentration-enhancement provided by thecompositions of the present invention may be determined in in vitrodissolution tests in an appropriate use environment. It has beendetermined that enhanced drug concentration in in vitro dissolutiontests in a buffer solution is a good indicator of in vivo performanceand bioavailability. One appropriate buffer solution is a PBS solution,which consists of 20 mM sodium phosphate (Na₂HPO₄), 47 mM potassiumphosphate (KH₂PO₄), 87 mM NaCl, and 0.2 mM KCl, adjusted to pH 6.5 withNaOH. Another appropriate buffer solution is a MOPS solution, whichconsists of 50 mM 4-morpholinepropanesulfonic acid (MOPS) with 150 mMNaCl, adjusted to pH 7.4 with NaOH. In particular, a composition of thepresent invention may be dissolution-tested by adding it to either a PBSsolution or a MOPS solution and agitating to promote dissolution. Acomposition of the invention is one that meets the criteria set outbelow when dosed to either solution.

Alternatively, the compositions comprising an adsorbate and a lipophilicmicrophase forming material provide concentration enhancement byreducing the mass of precipitate formed in the use environment relativeto the control composition. Reducing the mass of precipitate results inan increase in the amount of drug present in drug forms that are morelabile and mobile, resulting in an increase in relative bioavailability.As used herein, the “precipitate ratio” is defined as the mass of drugpresent in the precipitate obtained when a first control composition(e.g., the adsorbate alone) is administered to an aqueous useenvironment divided by the mass of drug present in the precipitateobtained when a test composition comprising the adsorbate and lipophilicmicrophase-forming material is administered to an equivalent amount ofthe same use environment. Thus, if 30 mg of drug is present in theprecipitate formed when a control composition is administered to a testmedium and 20 mg of drug is present in the precipitate formed when atest composition is administered to the same test medium, theprecipitate ratio is equal to 1.5 (30/20). The compositions comprisingan adsorbate and a lipophilic microphase forming material, followingintroduction to an aqueous environment of use, provide a precipitateratio that is at least 1.25 relative to the first control compositionpreviously described. Preferably, the composition of the presentinvention provides a precipitate ratio that is at least 2-fold, morepreferably at least 3-fold relative to the control composition.

The amount of drug present in precipitate may be determined by anyanalytical technique that can quantitatively make such a determination.In one method, the amount of drug present in precipitate is determinedby subtracting the total dissolved drug concentration from thetheoretical concentration of drug if all of the drug added to the testmedium had dissolved. As used herein, the term “total dissolved drug”refers to the total amount of drug dissolved in the aqueous solution,and includes drug present in the form of free drug, micelles, andlipophilic microphases. Specifically, this means that total dissolveddrug may be determined by separating out any undissolved drug bycentrifugation or filtration and then measuring the amount of drugremaining in the supernatant or filtrate. Total dissolved drug istypically taken as that material that either passes a 0.45 μm syringefilter or, alternatively, the material that remains in the supernatantfollowing centrifugation. Filtration can be conducted using a 13 mm,0.45 μm polyvinylidine difluoride syringe filter sold by ScientificResources under the trademark TITAN®. Centrifugation is typicallycarried out in a polypropylene microcentrifuge tube by centrifuging at13,000 G for 60 seconds. Other similar filtration or centrifugationmethods can be employed and useful results obtained. For example, usingother types of microfilters may yield values somewhat higher or lower(≈10-40%) than that obtained with the filter specified above but willstill allow identification of preferred compositions.

Alternatively, drug in precipitate may be determined by collecting thesolids obtained upon centrifugation or filtration of the aqueoussolution, dissolution of the solids in an appropriate solvent, such asmethanol, dimethylsulfoxide, or dimethylacetamide, and then analyzingfor the drug using any quantitative analytical technique such as HPLC orNMR.

In another alternative aspect, the composition comprising an adsorbateand a lipophilic microphase forming material may provide a maximum totaldissolved drug concentration (MDC) that is at least 1.25-fold the MDC ofeither the first control composition or the second control composition.In other words, if the MDC provided by either control composition is 100μg/mL, then a composition comprising an adsorbate and lipophilicmicrophase-forming material provides a MDC of at least 125 μg/mL. Morepreferably, the MDC of drug achieved with the compositions of thepresent invention are at least 2-fold, and even more preferably at least3-fold, that of either control composition. To facilitate testing, themaximum drug concentration may be taken as the maximum concentrationachieved within 90 to 180 minutes following administration of the drug.Preferred compositions meet these criteria for both the first controlcomposition and the second control composition:

Alternatively, the compositions comprising an adsorbate and a lipophilicmicrophase-forming material may provide in an aqueous use environment atotal dissolved drug concentration versus time Area Under The Curve(AUC), for any period of at least 90 minutes between the time ofintroduction into the use environment and about 270 minutes followingintroduction to the use environment that is at least 1.25-fold that ofeither the first control composition or the second control composition.More preferably, the AUC achieved with the compositions of the presentinvention are at least 2-fold and more preferably at least 3-fold thatof either control composition. Preferred compositions meet thesecriteria for both the first control composition and the second controlcomposition.

In a particularly preferred embodiment of the present invention, theinventors have found that certain compositions provide a surprisingly“synergistic enhancement” in the various concentration andbioavailability criteria described above. The “synergistic enhancement”is determined by comparing the performance of the test composition ofadsorbate and lipophilic microphase-forming material to a “third controlcomposition.” The third control composition consists essentially of theundispersed drug alone in its thermodynamically lowest energy state,typically the most stable crystalline form or its amorphous form if acrystalline form is unknown. Preferred compositions of drug/substrateadsorbate and lipophilic microphase-forming material exhibit synergisticenhancement by performing better than would be expected by simply addingthe enhancement provided by an adsorbate with the enhancement providedby the lipophilic microphase-forming material.

To determine synergy, it is necessary to determine the performance ofthe first control composition, the second control composition, and thethird control composition either in in vivo or in in vitro dissolutiontests. The relative enhancement of the first control composition (e.g.,the adsorbate but with no lipophilic microphase-forming material) isdetermined with respect to the third control composition. For example,if the first control composition provides an AUC₉₀ (that is, the AUCobtained during the first 90 minutes following introduction of thecomposition to a use environment) of 20,000 min*μg/ml and the thirdcontrol composition provides an AUC₉₀ of 1,000 min*μg/ml, the firstcontrol composition has a relative enhancement of 20-fold.

Likewise, the relative enhancement of the second control composition(e.g., the crystalline drug alone with lipophilic microphase-formingmaterial) is determined with respect to the third control composition.For example, if the second control composition provides an AUC₉₀ of40,000 min*μg/ml and the third control composition provides an AUC₉₀ of1,000 min*μg/ml, the second control composition has a relativeenhancement of 40-fold.

Compositions of the present invention provide synergistic enhancementwhen the relative enhancement provided by the test composition comparedwith the third control composition is greater than the sum of therelative enhancement provided by the first control composition and therelative enhancement provided by second control composition. Returningto the examples described above, if the first control compositionprovided a relative enhancement of 20-fold, and the second controlcomposition provided a relative enhancement of 40-fold, the sum of theirrelative enhancements would be 60-fold. Thus, a test compositionprovides synergistic enhancement when it provides a relative enhancementof greater than 60-fold compared with the third control composition.

The synergistic enhancement may also be determined by comparing therelative bioavailability of the test composition, first controlcomposition, and second control composition relative to the thirdcontrol composition. Synergistic enhancement would be shown where therelative bioavailability of the test composition is greater than the sumof the relative bioavailability of the first control composition and therelative bioavailability of the second control composition. For example,if the first control composition provides a relative bioavailability of1.5 with respect to the third control composition, and the secondcontrol composition provides a relative bioavailability of 2.0 withrespect to the third control composition, the test composition showssynergistic enhancement when it has a relative bioavailability relativeto the third control composition greater than 3.5.

Excipients and Dosage Forms

Although the key ingredients present in the compositions are simply (1)the drug/substrate adsorbate, (2) the lipophilic microphase-formingmaterial, and (3) the optional concentration-enhancing polymer, theinclusion of other excipients in the composition may be useful. Theseexcipients may be utilized in order to formulate the composition intotablets, capsules, suppositories, suspensions, powders for suspension,creams, transdermal patches, depots, and the like.

Conventional matrix materials, complexing agents, fillers,disintegrating agents (disintegrants), or binders may be added as partof the composition itself or added by granulation via wet or mechanicalor other means. These materials may comprise up to 90 wt % of thecomposition.

Examples of matrix materials, fillers, or diluents include lactose,mannitol, xylitol, microcrystalline cellulose, dibasic calcium phosphate(dihydrate and anhydrous), and starch.

Examples of disintegrants include sodium starch glycolate, sodiumalginate, carboxy methyl cellulose sodium, methyl cellulose, andcroscarmellose sodium, and crosslinked forms of polyvinyl pyrrolidonesuch as those sold under the trade name CROSPOVIDONE (available fromBASF Corporation).

Examples of binders include methyl cellulose, microcrystallinecellulose, starch, and gums such as guar gum, and tragacanth.

Examples of lubricants include magnesium stearate, calcium stearate, andstearic acid.

Examples of preservatives include sulfites (an antioxidant),benzalkonium chloride, methyl paraben, propyl paraben, benzyl alcoholand sodium benzoate.

Examples of suspending agents or thickeners include xanthan gum, starch,guar gum, sodium alginate, carboxymethyl cellulose, sodium carboxymethylcellulose, methyl cellulose, hydroxypropyl methyl cellulose, polyacrylicacid, silica gel, aluminum silicate, magnesium silicate, and titaniumdioxide.

Examples of anticaking agents or fillers include silicon oxide andlactose.

Other conventional excipients may be employed in the compositions ofthis invention, including those excipients well-known in the art.Generally, excipients such as pigments, lubricants, flavorants, and soforth may be used for customary purposes and in typical amounts withoutadversely affecting the properties of the compositions. These excipientsmay be utilized in order to formulate the composition into tablets,capsules, suspensions, powders for suspension, creams, transdermalpatches, and the like.

In particular, solid dosage forms such as immediate release tablets,controlled release tablets, delayed release tablets, chewable tabletsand analogous capsules containing solid material are a preferredembodiment of this invention. Preferred dosage forms of this typegenerally comprise from 10 wt % lipophilic microphase-forming materialup to 80 wt % lipophilic microphase-forming material as well as thedrug/substrate adsorbate, together with other optional excipients.

It is conventionally thought that because lipophilic microphase-formingmaterial are typically either low melting point or low T_(g) solids, oreven liquids at room temperature, that they are not consideredappropriate additives for such solid dosage forms except at low levels,typically less than about 5 wt % or less to promote wetting anddissolution of the tablet. However, the inventors have found that,contrary to such conventional wisdom, solid dosage forms with excellentproperties can be made that have relatively high levels of lipophilicmicrophase-forming material. In order for such high lipophilicmicrophase-forming material levels to be utilized in such solid dosageforms, the inventors have found it desirable to adsorb at least aportion of the lipophilic microphase-forming material on a solidsubstrate or disperse the lipophilic microphase-forming material in awater soluble or water dispersible matrix. As mentioned earlier,appropriate adsorption substrates include materials such as siliconoxide, dibasic calcium phosphate, microcrystalline cellulose, andcalcium silicate. Appropriate water soluble or water dispersibledispersion matrix materials include sugars such as sucrose and xylitol,organic acids such as citric acid or lactic acid, water soluble polymerssuch as polydextrose, polyethylene oxide, or dextrin. Particularlypreferred dispersion matrix materials are the concentration-enhancingpolymers previously described. In a particularly preferred embodiment,the lipophilic microphase-forming material is co-adsorbed along withdrug on a high surface area substrate. An added advantage of thisembodiment, particularly when the lipophilic microphase-forming materialis liquid at temperatures below about 50° C., is that relatively highlevels of lipophilic microphase-forming material, up to about 50 wt % orin some cases even more, can often be used while still having theresulting material be a solid powder or granule at ambient conditions.

Compositions of this invention may also be used in a wide variety ofdosage forms for administration of drugs. Exemplary dosage forms arepowders or granules that may be taken orally either dry or reconstitutedby addition of water or other liquids to form a paste, slurry,suspension or solution; tablets; capsules; multiparticulates; and pills.Various additives may be mixed, ground, or granulated with thecompositions of this invention to form a material suitable for the abovedosage forms. In one preferred embodiment, the drug/substrate adsorbateis dispersed in a vehicle that contains the lipophilicmicrophase-forming material.

The compositions of the present invention may be formulated in variousforms such that they are delivered as a suspension of particles in aliquid vehicle. Such suspensions may be formulated as a liquid or pasteat the time of manufacture, or they may be formulated as a dry powderwith a liquid, typically water, added at a later time but prior to oraladministration. Such powders that are constituted into a suspension areoften termed sachets or oral powder for constitution (OPC) formulations.Such dosage forms can be formulated and reconstituted via any knownprocedure. The simplest approach is to formulate the dosage form as adry powder that is reconstituted by simply adding water and agitating.Alternatively, the dosage form may be formulated as a liquid and a drypowder that are combined and agitated to form the oral suspension. Inyet another embodiment, the dosage form can be formulated as two powdersthat are reconstituted by first adding water to one powder to form asolution to which the second powder is combined with agitation to formthe suspension.

Generally, it is preferred that the composition be formulated forlong-term storage in the dry state as this promotes the chemical andphysical stability of the drug. Thus, a preferred embodiment is a soliddosage form comprising the adsorbate and lipophilic microphase-formingmaterial.

Yet another method to deliver the adsorbate and lipophilicmicrophase-forming material is to co-administer the adsorbate andlipophilic microphase-forming material to an in vivo use environment.The adsorbate and lipophilic microphase-forming material may each beadded separately to the in vivo use environment. Thus, when dosedorally, the adsorbate may be taken orally prior to the lipophilicmicrophase-forming material, at the same time, or after the lipophilicmicrophase-forming material has been taken orally. In general, ifadministered separately to an in vivo use environment, the adsorbate andthe lipophilic microphase-forming material should be administered withinabout 60 minutes of each other, preferably within about 30 minutes ofeach other, more preferably within about 15 minutes of each other.

Since the present invention has an aspect that relates to the treatmentof a condition or disorder by treatment with a combination of adrug/substrate adsorbate and a lipophilic microphase-forming materialthat may be co-administered separately, the invention also relates tocombining separate pharmaceutical compositions in kit form. The kitcomprises two separate pharmaceutical compositions: (1) a compositioncomprising the drug/substrate adsorbate; and (2) a compositioncomprising a lipophilic microphase-forming material. The amounts of (1)and (2) are such that, when co-administered separately, the condition ordisorder is treated and/or remediated. The kit comprises a container forcontaining the separate compositions such as a divided bottle or adivided foil packet, wherein each compartment contains a plurality ofdosage forms (e.g., tablets) comprising (1) or (2). Alternatively,rather than separating the active ingredient-containing dosage forms,the kit may contain separate compartments each of which contains a wholedosage which in turn comprises separate dosage forms. An example of thistype of kit is a blister pack wherein each individual blister containstwo (or more) tablets, one (or more) tablet(s) comprising pharmaceuticalcomposition (1), and the second (or more) tablet(s) comprisingpharmaceutical composition (2). Typically the kit comprises directionsfor the administration of the separate components. The kit form isparticularly advantageous when the separate components are preferablyadministered in different dosage forms (e.g., oral and parenteral), areadministered at different dosage intervals, or when titration of theindividual components of the combination is desired by the prescribingphysician. In the case of the instant invention a kit thereforecomprises

-   -   (1) a therapeutically effective amount of a composition        comprising a solid adsorbate of a low-solubility drug and high        surface area substrate, in a first dosage form;    -   (2) a therapeutically effective amount of a composition        comprising a lipophilic microphase-forming material, in a second        dosage form; and    -   (3) a container for containing said first and second dosage        forms.

An example of such a kit, alluded to above, is a so-called blister pack.Blister packs are well known in the packaging industry and are widelyused for the packaging of pharmaceutical unit dosage forms such astablets, capsules, and the like. Blister packs generally consist of asheet of relatively stiff material covered with a foil of a preferablytransparent plastic material. During the packaging process recesses areformed in the plastic foil. The recesses have the size and shape of thetablets or capsules to be packed. Next, the tablets or capsules areplaced in the recesses and the sheet of relatively stiff material issealed against the plastic foil at the face of the foil which isopposite from the direction in which the recesses were formed. As aresult, the tablets or capsules are sealed in the recesses between theplastic foil and the sheet. Preferably, the strength of the sheet issuch that the tablets or capsules can be removed from the blister packby manually applying pressure on the recesses whereby an opening isformed in the sheet at the place of the recess. Tablet(s) or capsule(s)can then be removed via said opening.

It may be desirable to provide a memory aid on the kit, e.g., in theform of numbers next to the tablets or capsules whereby the numberscorrespond with the days of the regimen during which the tablets orcapsules so specified should be ingested. Another example of such amemory aid is a calendar printed on the card, e.g., as follows “FirstWeek, Monday, Tuesday, . . . etc. . . . Second Week, Monday, Tuesday, .. . ”, etc. Other variations of memory aids will be readily apparent. A“daily dose” can be a single tablet or capsule or several pills orcapsules to be taken on a given day. Also a daily dose of the firstcompound can consist of one tablet or capsule while a daily dose of thesecond compound can consist of several tablets or capsules and viceversa. The memory aid should reflect this.

Compositions of the present invention may be used to treat any conditionthat is subject to treatment by administering a drug.

Other features and embodiments of the invention will become apparentfrom the following examples that are given for illustration of theinvention rather than for limiting its intended scope.

EXAMPLES Adsorbate 1

The following process was used to form a drug/substrate adsorbatecontaining 50 wt % [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester, “Drug 1”, and 50 wt % CAB-O-SIL M-5P (fumed silicafrom Cabot Corporation, Midland, Mich.) as a substrate (surface area ofabout 200 m²/gm). First, a spray solution was formed containing 10 gDrug 1, 10 g CAB-O-SIL, and 380 g acetone as follows. CAB-O-SIL wasadded to acetone and the mixture was sonicated using a Fisher ScientificSF15 sonicator for 30 minutes to ensure full suspension and homogeneity.Drug 1 was then dissolved in this suspension by stirring for 15 minutes.The spray solution was pumped using a Bran+Luebbe small volumehigh-pressure pump, to a spray drier (a Niro type XP PortableSpray-Dryer with a Liquid-Feed Process Vessel (“PSD-1”)), equipped witha pressure nozzle (Spraying Systems Pressure Nozzle and Body) (SK80-16). The PSD-1 was equipped with a 9-inch chamber extension. The9-inch chamber extension was added to the spray dryer to increase thevertical length of the dryer. The added length increased the residencetime within the dryer, which allowed the product to dry before reachingthe angled section of the spray dryer. The spray drier was also equippedwith a 316 SS circular diffuser plate with 1/16-inch drilled holes,having a 1% open area. This small open area directed the flow of thedrying gas to minimize product recirculation within the spray dryer. Thenozzle sat flush with the diffuser plate during operation. Thehigh-pressure pump was followed by a pulsation dampener to minimizepulsation at the nozzle. The spray solution was pumped to the spraydrier at a pressure of 350 psig. Drying gas (nitrogen) was circulatedthrough the diffuser plate at an inlet temperature of 100° C. Theevaporated solvent and wet drying gas exited the spray drier at atemperature of 34.5° C. The drug/substrate adsorbate formed by thisprocess was collected in a cyclone, and was post-dried using a Gruenbergsingle-pass convection tray dryer operating at 30° C. for 16 hours.

Example 1 In Vitro Dissolution Test

This test demonstrates the present invention in vitro. Example 1consisted of Adsorbate 1 administered in solution with a lipophilicmicrophase-forming material. At time 0, a 4 mg sample of Adsorbate 1 wasadded to 40 mL phosphate buffered saline (PBS) at pH 6.5 and 290mOsm/kg, containing 1 mg/mL of the lipophilic microphase-formingmaterial Cremaphor RH40 (available from BASF of Mount Olive, N.J.). Theconcentration of drug would have been 50 μg/mL, if all of the drug haddissolved. The test solution was stirred at room temperature in asyringe equipped with a Gelman Acrodisc 13 CR 0.45 μm PTFE filter. Ateach sample time, 1 to 2 mL test solution was pushed through the filterand analyzed using UV to determine the concentration of Drug 1 insolution. Samples were collected at 0.5, 1, 2, 3, 5, 10, 15, 20, 30, 45,60, 90, 120, 150, 250 and 1200 minutes. The results are shown in Table1.

Control 1

Control 1 consisted of Adsorbate 1 administered into PBS without thelipophilic microphase-forming material, and a sufficient amount ofadsorbate was added so that the concentration of drug would have been 50μg/mL, if all of the drug had dissolved. An in vitro dissolution testwas performed with Control 1 using the procedures outlined for Example 1and the results are shown in Table 1.

Control 2

Control 2 consisted of crystalline Drug 1 administered into PBScontaining 1 mg/mL of the lipophilic microphase-forming materialCremophor RH40, and a sufficient amount of Drug 1 was added so that theconcentration would have been 50 μg/mL, if all of the drug haddissolved. An in vitro dissolution test was performed with Control 2using the procedures outlined for Example 1 and the results are shown inTable 1.

Control 3

Control 3 consisted of crystalline Drug 1 administered into PBS withoutthe lipophilic microphase-forming material, and a sufficient amount ofcrystalline Drug 1 was added so that the concentration of drug wouldhave been 50 μg/mL, if all of the drug had dissolved. An in vitrodissolution test was performed with Control 3 using the proceduresoutlined for Example 1 and the results are shown in Table 1.

TABLE 1 Drug 1 Time Concentration AUC Example (min) (μg/mL) (min *μg/mL) 1 0 <0.5 0 0.5 <0.5 0 1 <0.5 <1 2 <0.5 <1 3 0.6 2 5 1.2 3 10 2.914 15 3.5 30 20 4.8 50 30 6.9 109 45 9.8 234 60 12.3 400 90 17.0 840 12018.3 1370 150 20.9 1960 250 22.2 4120 1200 10.5 18,500 Control 1 0 <0.50 0.5 <0.5 0 1 <0.5 <1 2 <0.5 <1 3 <0.5 <2 5 <0.5 <3 10 <0.5 <5 15 <0.5<8 20 <0.5 <10 30 <0.5 <15 45 <0.5 <23 60 <0.5 <30 90 <0.5 <45 120 <0.5<60 150 <0.5 <75 Control 2 0 <0.5 0 0.5 <0.5 0 1 <0.5 <1 2 <0.5 <1 3<0.5 <2 5 <0.5 <3 10 <0.5 <5 15 <0.5 <8 20 <0.5 <10 30 <0.5 <15 45 <0.5<23 60 0.7 31 90 1.0 56 120 1.1 88 250 2.2 307 1200 4.3 3400 Control 3 0<0.5 0 1 <0.5 <1 3 <0.5 <2 5 <0.5 <3 10 <0.5 <5 15 <0.5 <8 20 <0.5 <1030 <0.5 <15 45 <0.5 <23 60 <0.5 <30 90 <0.5 <45 120 <0.5 <60 1200 <0.5<600

The results of these tests are summarized in Table 2, which shows themaximum concentration of Drug 1 in solution during the first 90 minutesof the test (MDC₉₀), and the area under the aqueous concentration versustime curve after 90 minutes (AUC₉₀).

TABLE 2 MDC₉₀ AUC₉₀ Example (μg/mL) (min * μg/mL) 1 17.0 840 Control 1<0.5 <45 Control 2 1.0  56 Control 3 <0.5 <45

These results show that the compositions of the present inventionprovided enhancement over the compositions of Controls 1, 2, and 3.Example 1 provided a MDC₉₀ that was at least greater than 34.0-fold thatof Control 1, 17.0-fold that of Control 2, and at least greater than34.0-fold that of Control 3. Example 1 also provided an AUC₉₀ that wasat least greater than 18.7-fold that of Control 1, 15.0-fold that ofControl 2, and at least greater than 18.7-fold that of Control 3.

Example 2 In Vitro Dissolution Test

Example 2 consisted of Adsorbate 1 administered in solution with adifferent lipophilic microphase-forming material. At time 0, a 4 mgsample of Adsorbate 1 was added to 40 mL phosphate buffered saline (PBS)at pH 6.5 and 290 mOsm/kg, containing 1 mg/mL of 5/2 (wt/wt) CremaphorRH40/Capmul MCM (available from Abitec of Janesville, Wis.); theconcentration of drug would have been 50 μg/mL, if all of the drug haddissolved. The test solution was stirred at room temperature in asyringe equipped with a Gelman Acrodisc 13 CR 0.45 μm PTFE filter, asdescribed for Example 1. Samples were collected and analyzed using UV todetermine the concentration of Drug 1 in solution. The results are shownin Table 3.

Control 4

Control 4 consisted of crystalline Drug 1 administered into PBScontaining 5/2 (wt/wt) Cremophor RH40/Capmul MCM, and a sufficientamount of Drug 1 was added so that the concentration would have been 50μg/mL, if all of the drug had dissolved. The results are shown in Table3.

TABLE 3 Drug 1 Time Concentration AUC Example (min) (μg/mL) (min *μg/mL) 2 0 <0.5 0 0.5 <0.5 0 1 <0.5 <1 2 <0.5 <1 3 <0.5 <2 5 0.8 3 102.2 10 15 4.1 26 20 4.7 48 30 6.3 103 45 8.8 216 60 11.1 364 90 15.3 761120 17.7 1260 150 19.1 1810 300 19.9 4650 1380 10.1 20,900 Control 4 0<0.5 0 0.5 <0.5 0 1 <0.5 <1 2 <0.5 <1 3 <0.5 <2 5 <0.5 <3 10 <0.5 <5 15<0.5 <8 20 <0.5 <10 30 0.8 17 45 0.7 28 60 1.0 40 90 0.9 68 120 1.2 99150 1.5 140 300 1.5 340 1380 5.4 4050

The results of these tests are summarized in Table 4, which shows themaximum concentration of Drug 1 in solution during the first 90 minutesof the test (MDC₉₀), and the area under the aqueous concentration versustime curve after 90 minutes (AUC₉₀). Controls 1 and 3 are shown againfor comparison.

TABLE 4 MDC₉₀ AUC₉₀ Example (μg/mL) (min * μg/mL) 2 15.3 761 Control 40.9  68 Control 1 <0.5 <45 Control 3 <0.5 <45

These results show that the concentrations provided by the presentinvention were much greater than the concentrations provided by thecontrols. Example 2 provided a MDC₉₀ that was 17.0-fold that of Control4, at least greater than 30.6-fold that of Control 1, and at leastgreater than 30.6-fold that of Control 3. Example 2 also provided anAUC₉₀ that was 11.2-fold that of Control 4, at least greater than16.9-fold that of Control 1, and at least greater than 16.9-fold that ofControl 3.

Adsorbate 2

The following process was used to form a drug/substrate adsorbatecontaining 30 wt % [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester, “Drug 2”, and 70 wt % CAB-O-SIL M-5P as asubstrate. First, a spray solution was formed containing 122.0 mg Drug2, 200.7 mg CAB-O-SIL M-5P, and 20 g acetone as follows. CAB-O-SIL wasadded to acetone and the mixture was sonicated using a Fisher ScientificSF15 sonicator for 30 minutes to ensure full suspension and homogeneity.Drug 2 was then dissolved in this suspension by stirring for 15 minutes.This suspension was then pumped into a “mini” spray-drying apparatus viaa Cole Parmer 74900 series rate-controlling syringe pump at a rate of1.0 mL/min. The spray-drying apparatus used a Spraying Systems Co.two-fluid nozzle, model number SU1A, with nitrogen as the atomizing gas.The nitrogen was pressurized and heated to a temperature of 55° C. andhad a flow rate of about 1 standard ft³/min (SCFM). The suspension wassprayed from the top of an 11-cm diameter stainless steel chamber. Theresulting drug/substrate adsorbate was collected on Whatman 1 filterpaper, dried under vacuum, and stored in a desiccator.

Example 3 In Vitro Dissolution Test

Example 3 consisted of Adsorbate 2 administered into solution with alipophilic microphase-forming material. At time 0, a 6.656 mg sample ofAdsorbate 2 was added to 40 mL of phosphate buffered saline (PBS) at pH6.5 and 290 mOsm/kg, containing 1 mg/mL of PEG 6000 distearate (theconcentration of drug would have been 50 μg/mL, if all of the drug haddissolved). The test solution was stirred at room temperature in asyringe equipped with a Gelman Acrodisc 13 CR 0.45 μm PTFE filter, asdescribed for Example 1. Samples were collected and analyzed using UV todetermine the concentration of Drug 2 in solution. The results are shownin Table 5.

Control 5

Control 5 consisted of Adsorbate 2 administered into PBS without thelipophilic microphase-forming material, and a sufficient amount ofsample was added so that the concentration of drug would have been 50μg/mL, if all of the drug had dissolved.

Control 6

Control 6 consisted of crystalline Drug 2 administered into PBScontaining PEG 6000 Distearate, and a sufficient amount of Drug 2 wasadded so that the concentration would have been 50 μg/mL, if all of thedrug had dissolved.

Control 7

Control 7 consisted of crystalline Drug 2 administered into PBS withoutthe lipophilic microphase-forming material, and a sufficient amount ofsample was added so that the concentration of drug would have been 50μg/mL, if all of the drug had dissolved.

TABLE 5 Drug 2 Time Concentration AUC Example (min) (μg/mL) (min *μg/mL) 3 0 <0.5 0 0.5 <0.5 0 1 0.7 1 2 1.2 1 3 1.6 3 5 1.8 6 10 2.0 1615 2.5 27 20 2.4 39 30 2.7 65 45 2.7 105 60 3.0 147 90 3.2 239 Control 50 <0.5 0 60 <0.5 <30 120 <0.5 <60 210 <0.5 <105 1200 1.0 823 Control 6 0<0.5 0 0.5 <0.5 0 1 <0.5 <1 2 <0.5 <1 3 <0.5 <2 5 <0.5 <3 10 <0.5 <5 15<0.5 <8 20 <0.5 <10 30 <0.5 <15 45 <0.5 <23 60 <0.5 <30 90 <0.5 <45Control 7 0 <0.5 0 1 <0.5 <1 2 <0.5 <1 3 <0.5 <2 5 <0.5 <3 10 <0.5 <5 15<0.5 <8 20 <0.5 <10 30 <0.5 <15 45 <0.5 <23 64 <0.5 <32 90 <0.5 <45 160<0.5 <80 1200 <0.5 <600

The results of these tests are summarized in Table 6, which shows themaximum concentration of Drug 2 in solution during the first 90 minutesof the test (MDC₉₀), and the area under the aqueous concentration versustime curve after 90 minutes (AUC₉₀).

TABLE 6 MDC₉₀ AUC₉₀ Example (μg/mL) (min * μg/mL) 3 3.2 239 Control 5<0.5 <45 Control 6 <0.5 <45 Control 7 <0.5 <45

These results show that the concentrations provided by the presentinvention were much greater than the concentrations provided by thecontrols. Example 3 provided a MDC₉₀ that was at least greater than6.4-fold that of Control 5, at least greater than 6.4-fold that ofControl 6, and at least greater than 6.4-fold that of Control 7. Example3 also provided an AUC₉₀ that was at least greater than 5.3-fold that ofControl 5, at least greater than 5.3-fold that of Control 6, and atleast greater than 5.3-fold that of Control 7.

Adsorbate 3

The following process was used to form a drug/substrate adsorbatecontaining 25 wt %5-(2-(4-(3-benzisothiazolyl)piperazinyl)ethyl-6-chlorooxindole, “Drug3”, and 75 wt % CAB-O-SIL M-5P as a substrate. A spray solution wasformed containing 62.5 mg Drug 3, 187.5 mg CAB-O-SIL M-5P, and 40 gacetone/water (9/1), and spray dried using the “mini” spray-dryingapparatus described for Adsorbate 2. The suspension was pumped into the“mini” spray drier at a rate of 1.3 mL/min, and the nitrogen atomizinggas was heated to a temperature of 70° C.

Example 4 In Vitro Dissolution Test

Example 4 consisted of Adsorbate 3 administered into solution with alipophilic microphase-forming material. At time 0, an 8.02 mg sample ofAdsorbate 3 was added to 40 ml of 50 mM 3-(4-morpholino propane sulfonicacid) sodium salt (MOPS) buffer at pH 7.4, containing 5 mg/mL of Tween80 (available from ICI Americas Inc); the concentration of drug wouldhave been 50 μg/mL, if all of the drug had dissolved. The test solutionwas stirred at room temperature in a syringe equipped with a GelmanAcrodisc 13 CR 0.45 μm PTFE filter, as described for Example 1. Sampleswere collected and analyzed using UV to determine the concentration ofDrug 3 in solution. The results are shown in Table 7.

Control 8

Control 8 consisted of Adsorbate 3 administered into PBS without thelipophilic microphase-forming material, and a sufficient amount ofsample was added so that the concentration of drug would have been 50μg/mL, if all of the drug had dissolved.

Control 9

Control 9 consisted of crystalline Drug 3 administered into PBScontaining Tween 80, and a sufficient amount of Drug 3 was added so thatthe concentration would have been 50 μg/mL, if all of the drug haddissolved.

Control 10

Control 10 consisted of crystalline Drug 3 administered into PBS withoutthe lipophilic microphase-forming material, and a sufficient amount ofsample was added so that the concentration of drug would have been 50μg/mL, if all of the drug had dissolved.

TABLE 7 Drug 3 Time Concentration AUC Example (min) (μg/mL) (min *μg/mL) 4 0 0 0 0.5 17 4 1 15 12 2 12 26 3 11 37 5 9 57 10 9 101 15 7 14020 6 173 30 6 232 45 5 315 60 5 395 90 5 545 120 5 690 1250 4 5640Control 8  0 <1 0 0.5 <1 <1 1 <1 <1 2 <1 <2 3 <1 <3 5 <1 <5 15 <1 <15 20<1 <20 30 <1 <30 45 <1 <45 60 <1 <60 84 <1 <84 150 <1 <150 Control 9  0<1 0 0.5 <1 <1 1 <1 <1 2 <1 <2 3 <1 <3 5 <1 <5 10 <1 <10 15 <1 <15 20 <1<20 30 <1 <30 45 1 45 60 1 60 90 2 120 1245 2 2430 Control 10 0 <1 <1 5<1 <5 10 <1 <10 20 <1 <20 40 <1 <40 90 <1 <90 1260 <1 <1260

The results of these tests are summarized in Table 8, which shows themaximum concentration of Drug 3 in solution during the first 90 minutesof the test (MDC₉₀), and the area under the aqueous concentration versustime curve after 90 minutes (AUC₉₀).

TABLE 8 MDC₉₀ AUC₉₀ Example (μg/mL) (min * μg/mL) 4 17 545 Control 8  <1<90 Control 9   2 120 Control 10 <1 <90

These results show that the concentrations provided by the presentinvention were much greater than the concentrations provided by thecontrols. Example 4 provided a MDC₉₀ that was at least greater than17.0-fold that of Control 8, 8.5-fold that of Control 9, and at leastgreater than 17.0-fold that of Control 10. Example 4 also provided anAUC₉₀ that was at least greater than 6.1-fold that of Control 8,4.5-fold that of Control 9, and at least greater than 6.1-fold that ofControl 10.

The terms and expressions which have been employed in the foregoingspecification are used therein as terms of description and not oflimitation, an there is no intention, in the use of such terms andexpressions, of excluding equivalents of the features shown anddescribed or portions thereof, it being recognized that the scope of theinvention is defined and limited only by the claims which follow.

The invention claimed is:
 1. A composition comprising: (a) a spray-driedsolid dispersion adsorbate comprising a completely amorphous drug and aconcentration enhancing polymer adsorbed onto an inorganic oxidesubstrate, and wherein said drug in said adsorbate is substantiallycompletely amorphous and (b) a lipophilic microphase-forming materialselected from the group consisting of medium-chain glyceryl mono-, di-,and tri-alkylates, sorbitan esters, sorbitan fatty acid esters,polyoxyethylene sorbitan fatty acid esters, alpha tocopherylpolyethylene glycol 1000 succinate (TPGS), and mixtures thereof; saidcomposition having a mass ratio of said lipophilic microphase-formingmaterial to said drug of from 0.1 to 500, and wherein said lipophilicmicrophase forming material is co-adsorbed with said drug onto saidsubstrate of the spray-dried solid dispersion adsorbate; wherein saidlipophilic microphase-forming material is water immiscible and said drughas a partition coefficient K_(p) between a use environment and saidlipophilic microphase-forming material of about 10 or more.
 2. Thecomposition of claim 1 wherein said lipophilic microphase-formingmaterial is present in a sufficient amount so that said compositionprovides concentration enhancement of said drug in a use environmentrelative to at least one of a first control composition and a secondcontrol composition; wherein (i) said first control composition consistsessentially of an equivalent amount of said solid adsorbate with nolipophilic microphase-forming material present; (ii) said second controlcomposition consists essentially of an equivalent amount of said drug inunadsorbed form with an equivalent amount of said lipophilic,microphase-forming material.
 3. The composition of claim 2 wherein saidcomposition provides a relative bioavailability of at least 1.25-foldrelative to at least one of said first control composition and saidsecond control composition.
 4. The composition of claim 1 wherein saidlipophilic microphase-forming material forms lipophilic microphases insaid use environment having a characteristic diameter of less than about100 μm.
 5. The composition of claim 1 wherein said mass ratio of saidlipophilic microphase-forming material to said drug is from 0.1 to 100.6. The composition of claim 1 wherein said solid adsorbate and saidlipophilic microphase-forming material are both present in a singledosage form.
 7. The composition of claim 1 wherein said composition issolid at 25° C.
 8. The composition of claim 1 wherein said compositionprovides synergistic enhancement.
 9. The composition of claim 1 whereinsaid drug is selected from the group consisting of antihypertensives,antianxiety agents, anticlotting agents, anticonvulsants, bloodglucose-lowering agents, decongestants, antihistamines, antitussives,antineoplastics, beta blockers, anti-inflammatories, antipsychoticagents, cognitive enhancers, anti-atherosclerotic agents,cholesterol-reducing agents, antiobesity agents, autoimmune disorderagents, anti-impotence agents, antibacterial and antifungal agents,hypnotic agents, anti-Parkinsonism agents, anti-Alzheimer's diseaseagents, antibiotics, antidepressants, and antiviral agents, glycogenphosphorylase inhibitors, and cholesteryl ester transfer proteininhibitors.
 10. The composition of claim 1 wherein saidconcentration-enhancing polymer is selected from the group consisting ofhydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, cellulose acetatetrimellitate, carboxymethyl ethyl cellulose, hydroxypropyl methylcellulose, poloxamers, polyvinylpyrrolidone, polyvinyl alcohols thathave at least a portion of their repeat units in hydrolyzed form, andmixtures thereof.
 11. The composition of claim 1 further comprising asecond concentration-enhancing polymer wherein said second concentrationenhancing polymer is not adsorbed to said substrate.
 12. The compositionof claim 11 wherein said second concentration-enhancing polymer isselected from the group consisting of hydroxypropyl methyl celluloseacetate succinate, hydroxypropyl methyl cellulose phthalate, celluloseacetate phthalate, cellulose acetate trimellitate, carboxymethyl ethylcellulose, hydroxypropyl methyl cellulose, poloxamers,polyvinylpyrrolidone, polyvinyl alcohols that have at least a portion oftheir repeat units in hydrolyzed form, and mixtures thereof.
 13. A soliddosage form comprising the composition of claim 1, wherein saidlipophilic, microphase-forming material comprises from 10wt % to 80wt %10 wt % to 80 wt % of said solid dosage form, and said dosage form isselected from the group consisting of a tablet and a capsule.
 14. Thecomposition of claim 1 wherein said substrate is selected from the groupconsisting of SiO₂, TiO₂, ZnO₂, ZnO, Al₂O₃, MgAlSilicate, CaSilicate,AIOH₂ AlOH₂, zeolites, and inorganic molecular sieves.
 15. Thecomposition of claim 1 wherein said lipophilic microphase-formingmaterial is selected from sorbitan fatty acid esters, alpha tocopherylpolyethylene glycol 1000succinate 1000 succinate (TPGS), and mixturesthereof.
 16. The composition of claim 1 wherein said solid adsorbate isformed by spraying a spray suspension comprising said drug, saidlipophilic microphase-forming material, and said concentration-enhancingpolymer, dissolved in a solvent having said substrate suspended therein,and the solvent is removed to form a solid powder in less than 100seconds.